• Alzheimer’s disease;
  • Bri;
  • chaperone;
  • dementia;
  • lung fibrosis, proSP-C, protein misfolding


  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References

The BRICHOS domain was initially defined from sequence alignments of the Bri protein associated with familial dementia, chondromodulin associated with chondrosarcoma and surfactant protein C precursor (proSP-C) associated with respiratory distress syndrome and interstitial lung disease (ILD). Today BRICHOS has been found in 12 protein families. Mutations in the Bri2 and proSP-C genes result in familial dementia and ILD, respectively, and both these conditions are associated with amyloid formation. Amyloid is of great medical relevance as it is found in several major incurable diseases, like Alzheimer’s and Parkinson’s disease and diabetes mellitus. Work on recombinant BRICHOS domains and transfected cells indicate that BRICHOS is a chaperone domain that, during biosynthesis, binds to precursor protein regions with high β-sheet propensities, thereby preventing them from amyloid formation. Regions prone to form β-sheets are present in all BRICHOS-containing precursor proteins and are probably eventually released by proteolytic cleavage, generating different peptides with largely unknown bioactivities. Recombinant BRICHOS domains from Bri2 and proSP-C have been found to efficiently prevent SP-C, the amyloid β-peptide associated with Alzheimer’s disease, and medin, found in aortic amyloid, from forming amyloid fibrils. The data collected so far on BRICHOS raise several interesting topics for further research: (a) amyloid formation is a potential threat for many more proteins than the ones recognized so far in amyloid diseases; (b) amyloid formation of widely different peptides involves intermediate(s) that are recognized by the BRICHOS domain, suggesting that they have distinct structural similarities; and (c) the BRICHOS domain might be harnessed in therapeutic strategies against amyloid diseases.


amyloidogenic peptide in FBD


amyloidogenic peptide in FDD


amyloid precursor protein




endoplasmic reticulum


familial British dementia


familial Danish dementia




human embryonic kidney


heat shock protein


interstitial lung disease


Leu, Ala, Met


prosurfactant protein C


respiratory distress syndrome


trefoil factor family






Val, Ile, Phe and Cys


  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References

In 2002 Sanchez-Pulido and coworkers discovered, by the use of bioinformatics tools, the BRICHOS domain, so called from the first letters in the BRICHOS-containing proteins Bri2, related to familial British and Danish dementia (FBD and FDD), chondromodulin, related to chondrosarcoma, and prosurfactant protein C (proSP-C), related to respiratory distress syndrome (RDS) and interstitial lung disease (ILD) [1]. The authors predicted the domain to be linked to complex post-translational processing of these proteins, e.g. as an intramolecular chaperone [1]. In 2009, Hedlund and coworkers [2] found the BRICHOS domain to be present in more than 300 proteins, divided into 12 distantly related families.

The BRICHOS domain consists of ∼ 100 amino acids, and the different BRICHOS-containing proteins show a conserved pattern comprising a cytosolic part, a hydrophobic domain, a linker region, a BRICHOS domain and a C-terminal region that contains at least two stretches with high predicted β-sheet propensities interrupted by a short coil region (Figs 1B and 2A). The hydrophobic domain in most BRICHOS-containing proteins, is known or predicted to be a single-pass transmembrane (TM) region, and the corresponding proteins adopt a type II orientation, i.e. the N-terminus is located in the cytosol. For the gastrokines and arenicin, however, the hydrophobic regions may constitute signal peptides [3–5]. The only exception from the overall pattern of five regions is proSP-C, in which the BRICHOS domain constitutes the very C-terminal part of the protein, i.e. it lacks a C-terminal region with high β-sheet propensity. Strikingly, however, in proSP-C, unlike in all other BRICHOS-containing proteins, the TM region has a high β-sheet propensity (Fig. 1A). The different BRICHOS domains have a low overall amino acid sequence conservation with only three amino acid residues strictly conserved across the BRICHOS families, two Cys and one Asp. Their predicted secondary structures, however, are very similar [1,2], suggesting that the BRICHOS structure is largely preserved in all proteins identified so far. The two Cys form a disulfide bridge in proSP-C [6], and their strict conservation in the BRICHOS family suggests that the disulfide bridge is also present in all BRICHOS domains (Fig. 1).


Figure 1.  Schematic overview of the structural organization of BRICHOS-containing proteins. All BRICHOS-containing proteins are composed of an N-terminal region, a hydrophobic region, a linker region and the BRICHOS domain. In addition all BRICHOS proteins, except proSP-C (A), contain a C-terminal region (B). The C-terminal regions (B) contain at least two stretches with high β-strand propensities (indicated by red stripes), and likewise the TM region of proSP-C has high β-strand propensity (marked by red stripes); see further Fig. 2A. The different regions have different lengths in different BRICHOS-containing proteins and the hydrophobic region in (B) is in most cases a TM region but can in some cases be a signal peptide. See text for further details and references.

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Figure 2.  Regions with high β-strand propensities in proteins that contain or bind to BRICHOS. (A) Amino acid sequences of C-terminal regions, or TM part of proSP-C, of the indicated BRICHOS-containing proteins. The numbers indicate the first residue shown for the corresponding protein. Arrows above sequences mark stretches that are predicted to form β-strands [2], and black underlining marks regions that are biased for the amino acid residues V, I, F or C [90]. (B) NMR structure of the C-terminal region from arenicin, showing a strand–loop–strand conformation [4]. (C) NMR structure of TFF1 [92], which binds to GKN2 [3], showing a central strand–loop–strand structure (marked in blue).

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The suggested chaperone function of BRICHOS, supported by the possibility that it is structurally similar to the apical domain of GroEL [1], in combination with the presence of the highly β-sheet prone and amyloidogenic TM region of proSP-C [7–9], made us hypothesize that a physiological role of the proSP-C BRICHOS domain may be in preventing amyloid formation of the proSP-C TM region during biosynthesis [10–12]. In this review, we summarize the currently available experimental data on the function and structure of the BRICHOS domain from different proteins. We also discuss possible roles of the BRICHOS domain in health and disease, and propose a role of BRICHOS as a chaperone against β-sheet aggregation and amyloid fibril formation.


  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References

SP-C is a TM protein present in lung surfactant, which is responsible for lowering the surface tension of the alveolar air–water interface and, by doing so, preventing the lungs from collapsing at the end of expiration [13,14]. Mature SP-C is a 35-residue acylated peptide and forms an α-helix, which is discordant, i.e. it is composed of amino acids with a high β-strand propensity, primarily Ile and Val. Once the helix has formed and is inserted into the membrane, it is stable, but taken out of its phospholipid environment it can unfold and convert into β-sheet aggregates and amyloid-like fibrils [7–9,15,16]. However, the folding into an α-helix has proven to be a problem for poly-Val regions because of the low α-helical propensity [17]. Synthetic SP-C analogues with the poly-Val stretch cannot fold into an α-helix conformation but instead form insoluble aggregates, while a synthetic SP-C analogue with poly-Leu can fold into a stable helical conformation [18].

Nature has apparently solved the folding problem of SP-C by synthesizing it via a precursor protein, proSP-C. proSP-C is a 21 kDa (197 amino acid) type II membrane protein that contains four of the five regions typical of BRICHOS-containing proteins: a short N-terminal segment that is located in the cytosol and is important for intracellular trafficking, a TM region that makes up the main part of mature SP-C, a highly conserved linker region, followed by a BRICHOS domain that is located in the endoplasmic reticulum (ER) lumen. Expression of mature SP-C without its N- and/or C-terminal parts results in aggregation of mature protein in the secretory pathway, indicating that these segments are necessary for correct folding and/or proper intracellular targeting [19–21].

Mutations in the proSP-C gene results in ILD

Mutations in the proSP-C gene (SFTPC) are associated with ILD, with intracellular protein aggregates [22,23]. There are today about 50 such mutations, and the majority of them are located in the C-terminal part of the precursor protein (linker and BRICHOS domain). The mutations are found on one allele only; about half of them arise spontaneously and the rest are inherited. In general the age of onset varies from the newborn period to adulthood, and the phenotype differs between individuals even though they carry the same mutation [24].

The most common SFTPC mutation is I73T, located in the linker region of proSP-C. Staining of lung tissue from I73T patients with antibodies against proSP-C reveals diffuse cellular staining, which indicates that this mutation is associated with abnormal trafficking and accumulation of protein in early endosomal compartments. Incompletely processed proSP-C, together with mature SP-C, was found in bronchoalveolar lavage fluid from a patient with I73T mutation, and alveolar proteinosis was found histologically [25,26].

In patients with deletion of exon 4, decreased levels or even a total lack of mature SP-C are observed with disrupted lung morphology [23]. Transgenic expression of proSP-C(Δexon4) in cell lines has shown that this mutation causes misfolding of proSP-C, ER stress and induction of the unfolded protein response [27,28]. The L188Q mutation of proSP-C, like the Δexon4 mutation, is located in the BRICHOS domain, and transgenic expression of both the corresponding proteins in cells leads to intracellular accumulation of amyloid-like inclusions [12].


  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References

Bri2, also called integral transmembrane protein (ITM2B), is a type II transmembrane protein and the corresponding gene (ITM2B) belongs to a family containing also Bri1 (ITM2A) and Bri3 (ITM2C) [29–31]. The initially produced form of Bri2 is 266 residues long, and it is cleaved in the secretory pathway by furin between Arg243 and Glu244. This furin cleavage generates a 243-residue, membrane-bound mature Bri2 and a soluble 23-residue peptide (Bri23) [32–34]. The function of Bri2 is unknown, but it has been suggested that it has a role in neuronal differentiation [32] and as a tumour suppressor [35].

Bri2 is produced in several peripheral tissues and in the brain. In humans, it shows a significant expression in the neurons of the hippocampus and cerebellum [36,37]. The Bri23 peptide has been suggested as a biomarker candidate for cerebellar and cognitive dysfunction in multiple sclerosis [38].

Mutations in Bri2 results in familial dementia

Mutations in the Bri2 gene give rise to FBD and FDD. FBD is caused by a single base substitution in the stop codon, which leads to production of a C-terminally extended precursor protein (277 residues instead of 266). This in turn results in release of a 34-residue, amyloidogenic peptide (ABri), in which the first 23 residues are identical to the wild-type counterpart (Bri23 peptide), after furin cleavage [37].

FDD, on the other hand, is caused by a decamer duplication insertion between codons 265 and 266, which causes a shift in the reading frame, rendering the normal stop codon non-functional. The result, just as in FBD, is a larger precursor protein, where normal furin processing results in a 34 amino acid C-terminal peptide (ADan), which can aggregate and form amyloid fibrils in the central nervous system [39]. Residues 1–23 are identical in ABri and ADan, but the C-terminal 11 residues are completely different.

Several transgenic mouse models of FBD and FDD have been created. The models of FDD demonstrate similar pathological changes to the human diseases, with amyloid depositions in hippocampus, cortex and brainstem, often associated with the vasculature, and an inflammatory response [40–43]. Production of the ADan peptide also induces tau pathology, as in Alzheimer’s disease, suggesting a common pathophysiological mechanism for different amyloidogenic peptides [40,43]. However, recent knock-in models for FBD and FDD suggest that the British and Danish dementia could be due to a loss of Bri2 function rather than amyloidogenesis [44,45].

Bri2 and Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly [46]. The senile plaques found in the brain of patients with Alzheimer’s disease contain amyloid fibrils formed by Aβ. However, it is the polymerization of Aβ and formation of toxic oligomers, rather than the fibrils per se, that are believed to cause the disease. Many studies indicate that pre-fibrillar intermediates present during the aggregation process trigger neuronal dysfunction [47–51].

Several findings have pointed towards the importance of Bri2 in amyloid precursor protein (APP) processing. It has been shown that Bri2 can inhibit Aβ accumulation, both in vitro [52,53] and in vivo [40,41,54], and data supporting that the suppressive effect is due to the Bri23 peptide have been reported [54]. Bri2 and Aβ have also been found co-localized in the Alzheimer’s amyloid plaques, suggesting that they interact during the misfolding and aggregation process [55]. Moreover, Bri2 can affect the proteolytic processing of APP into Aβ, but in order to do so it first needs to be processed by furin. Although full-length Bri2 does not seem to interact with APP processing, both the mature Bri2 and the Bri23 peptide seem to do so, and thereby regulate Aβ production and aggregation. It has also been suggested that mature Bri2 inhibits APP processing by α-, β- and γ-secretases in the plasma membrane and in endocytic compartments [56]. Peng et al. [57] suggested that release of Bri23 has the result that the postulated peptide binding site in mature Bri2 becomes available for binding to other targets, such as Aβ and APP.

Proposed functions of the BRICHOS domain in different proteins

  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References

BRICHOS-containing proteins have so far been found in vertebrates, Drosophila, echinoderms, nematodes and lancelets. The 12 different family members in the BRICHOS family are proSP-C, group C (human protein referred to as BRICHOS-domain-containing protein C16orf79), GKN2, GKN1, GKN3 (formerly known as group B), LECT1, TNMD, a small divergent group of two uncharacterized proteins, group A, ITM2A, ITM2B and ITM2C [2]. Many of these proteins lack known functions and their expression patterns in many cases are not known. Table 1 summarizes known functions, processing enzymes and binding partners for the BRICHOS-containing proteins.

Table 1.   BRICHOS-containing proteins and their proposed functions, proteolytic enzymes that are involved in their processing, and identified binding partners to the BRICHOS domain. Furin cleavage sites were predicted by ProP [95] and are in some cases verified by experimental data; see text for details.
ProteinSynonymFunction/diseaseProcessing enzymesBinding targetReference
Bri1ITM2AChondrogenesis  [29,61]
Bri2ITM2BFBD, FDDFurin, ADAM, SPPLBri23, Aβ40, Aβ42[33,34,37,39,57,58]
Bri3ITM2C Furin [59]
GKN1 Mucosal protection  [63,64]
GKN2TFIZ1, blottin (mouse)Mucosal maintenance/tumour suppressor TFF1, TFF2 (mouse)[3,65]
GKN3 Host response to Helicobacter pylori (mouse)  [66]
ChM-ILECT1Anti-angiogenic in cartilage/chondrosarcomaFurin [67,68]
TNMDChM1LTenocyte proliferationFurin [69,70,96]
proSP-C Lung surfactant activity, ILD, RDSCathepsin HTransmembrane part of SP-C, Aβ40, medin[10,11,89,97]
Arenicin Antibacterial activity (C-terminal peptide)  [4]
Group A  Furin  
Group CC16orf79 (human)    


In vitro experiments have shown that the BRICHOS domain of proSP-C binds SP-C peptides in β-sheet conformations, but not helical SP-C, and that binding of BRICHOS to a non-helical peptide from SP-C results in α-helix formation [10,11]. In human embryonic kidney (HEK) 293 cells, expression in trans of the proSP-C BRICHOS domain carrying a signal peptide that directs it to the ER lumen stabilizes mutant proSP-C(L188Q) and prevents generation of amyloid-like inclusions of the mutant [12]. Expression of proSP-C1–58 (i.e. SP-C with its N-terminal propeptide) alone in HEK293 cells results in virtually no detectable protein, while co-expression in trans of proSP-C BRICHOS domain carrying a signal peptide yields non-aggregated and SDS-soluble proSP-C1–58, compatible with generation of α-helical SP-C [10]. These data suggest that the BRICHOS domain of proSP-C possesses a chaperone function for the TM part of proSP-C, preventing the poly-Val stretch from misfolding and aggregation and instead promoting α-helix formation [10,12].

Our recent unpublished results indeed show that loss of the BRICHOS chaperone function due to mutations in SFTPC leads to amyloid inclusions of SP-C protein in the lung of patients with ILD (H Willander, G Askarieh, M Landreh, P Westermark, K Nordling, H Keränen, E Hermansson, A Hamvas, LM Nogee, T Bergman, A Saenz, C Casals, J Åqvist, H Jörnvall, H Berglund, J Presto, SD Knight and J Johansson, unpublished results).


Processing of mature Bri2 by the metalloprotease ADAM10 causes a release of the BRICHOS domain from the N-terminal part, secretion of the BRICHOS domain into the extracellular space, and intramembrane proteolysis by SPPL2a/2b to release the intracellular domain [58]. The BRICHOS domain of Bri2 has been shown to bind to its C-terminal peptide Bri23 [57]. The exact substrate specificity of Bri2 BRICHOS is still not known; however, it was shown to bind segments where hydrophobic residues were flanked by charged residues [57].

Bri1 and Bri3

In contrast to the ubiquitous expression of Bri2, Bri3 (ITM2C) expression is found mainly in the brain [31], and furin, which processes Bri2, also cleaves Bri3 [59]. Bri3 has been shown to co-localize with APP in neurites and co-immunoprecipitation of Bri3 and APP has been demonstrated [60]. The N-terminal 130 amino acids of Bri3 are sufficient for APP binding, and thus the BRICHOS domain is not necessary for this interaction [60]. Overexpression of Bri3 reduces APP α- and β-secretase cleavage, and Bri3 knockdown by RNA interference in APP overexpressing HEK293 cells results in increased levels of soluble APP, Aβ40 and Aβ42 [60].

Bri1 (ITM2A) was originally cloned as a gene with strong expression in osteogenic tissue and muscle, and has been reported to be involved in the early stages of chondrogenesis [29,32,61]. Bri1 has further been shown to have an increased expression in T lymphocytes in the thymus and is localized to the Golgi apparatus, cytoplasmic vesicles and on the cell surface [62].


Three families of gastrokines (GKN1, GKN2 and group B) contain a BRICHOS domain, and two have been associated with gastric cancer (GKN1 and GKN2). GKN1 is expressed in gastric mucosa, but not in gastric carcinoma cells, and has a suggested role in mucosal protection [63,64].

GKN2, also called TFIZ1 and blottin (the mouse homologue), has been shown to interact with members of the trefoil factor family (TFF1 and TFF2), which are cancer associated. The human TFF1 forms a heterodimer with GKN2 [3], and blottin has been found to bind to TFF2 [65].

A novel gastrokine, GKN3 (group B), was recently found to be associated with gastric atrophy in mouse and possibly in the host response to Helicobacter pylori. However, humans seem to have lost GKN3 gene expression due to a mutation [66].

Chondromodulin-I and tenomodulin

The chondromodulin-I (ChM-I), also called leukocyte cell derived chemotaxin (LECT1), was one of the first proteins found containing a BRICHOS domain [1]. The 335 amino acid precursor protein of ChM-I (bovine) is post-translationally processed intracellularly into a 28 kDa glycosylated protein including its BRICHOS domain, and is found in lysates from cultured chondrocytes and secreted in media. The ChM-I is processed by furin, which cleaves the C-terminal domain of the protein, as for the processing of Bri2 [67].

ChM-I is associated with chondrosarcoma, and loss of its expression seems to be important for the angiogenic property related to the malignant transformation [68].

Tenomodulin (TNMD), also called chondromodulin-1 like protein (ChM1L), is expressed in eye, skeletal muscle, whole rib and dense connective tissue, and its expression is increased during mouse embryonic development [69,70].

Group C

The members of the group C family have only been studied at the gene or transcript levels, and the functions of these proteins are unknown. It is notable, however, that the sequence of the C-terminal region of group C, including four Cys, is strictly conserved, suggesting that it is functionally important [2]. Moreover, the Cys-containing regions contain two strongly predicted β-strands, suggesting that they can form a β-hairpin motif, although the hydrophobic nature of this region suggests that it can insert into membranes (Fig. 2A).

Anti-amyloid activity of proSP-C and Bri2 BRICHOS

  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References

Protein folding is a complicated process, and correct folding of a newly synthesized protein into its native state is essential. Molecular chaperones constitute one way of counteracting misfolding in the cell [71]. A specific form of protein misfolding underlies amyloid diseases, where specific proteins lose their native states and instead form amyloid fibrils, which are built from β-sheet polymers that apparently are very similar independently of which protein they are made from. Amyloid fibrils and/or their precursor forms are toxic and cause cell death. At least 27 amyloid diseases are known today, among them Alzheimer’s disease, prion diseases and type II diabetes mellitus [72]. Amyloid fibrils are straight, unbranched and show a cross-β X-ray diffraction pattern [73]; and in addition staining with the dye Congo Red should result in green birefringence under polarized light [72].

The molecular chaperones, small heat shock proteins (sHsps), Hsp20 and HspB8 are examples of chaperones that have been found to co-localize with amyloid plaques associated with Alzheimer’s disease and other neurodegenerative disorders [74]. This suggests that the cellular quality control machinery is activated in an attempt to prevent the accumulation of misfolded species [75]. Examples of molecular chaperones that affect fibril formation of Aβ (associated with Alzheimer’s disease) in vitro are Hsp70, Hsp90 and Hsp104 [76–79], and the sHsp αA-crystallin [80,81]. Hsp70 and Hsp104 also affect the aggregation of α-synuclein, which is the major component in the Lewy bodies, associated with Parkinson’s disease [82], and the yeast prion protein Sup35 [83].

Beyond the intracellular machinery of chaperones, the extracellular chaperones clusterin, haptoglobulin and α2-macroglobulin have been found to interact with misfolded proteins, preventing them from aggregation [84–86]. These extracellular chaperones have been associated with amyloid deposits, and clusterin can inhibit Aβ fibril formation by destabilization of pre-fibrillar species [84–87].

The BRICHOS domain of proSP-C has broad substrate specificity in terms of amino acid sequence and binds to stretches of all non-polar residues that promote membrane insertion; thus it specifically recognizes non-helical TM regions [88]. Aβ contains a TM region and a discordant helix, which means that it could be a possible target for the proSP-C BRICHOS chaperone. In line with this, electron microscopy and solubility assays of Aβ1–40 co-incubated with 1/10 of the BRICHOS domain of proSP-C showed that fibril formation is reduced by BRICHOS. Measuring the fibril formation of Aβ1–40 by thioflavin T fluorescence with and without proSP-C BRICHOS confirmed that the fibrillation process was delayed. Moreover, proSP-C BRICHOS was shown to form a complex with Aβ oligomers and also to inhibit fibril formation of medin, which forms amyloid in the aortic wall [89]. Bri2 BRICHOS likewise binds to Aβ1–40in vitro and inhibits its aggregation and fibril formation, so anti-amyloid activity against Aβ is inherent also in another BRICHOS domain [57].

Recent results have shown that the BRICHOS domains from Bri2 and proSP-C prevent Aβ fibril formation in a concentration-dependent manner, and far below stoichiometric amounts of BRICHOS are needed for efficient inhibition of Aβ40 (H Willander, J Presto, G Askarieh, B Frohm, SD Knight, J Johansson and S Linse, unpublished results).

Ability of BRICHOS to bind β-hairpin regions and implications for its function

  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References

The proSP-C BRICHOS domain is proposed to act as an intramolecular chaperone that promotes α-helical formation of the TM region, which exhibits high β-sheet propensity [10]. The Bri2 BRICHOS has been shown to bind its C-terminally derived peptide Bri23, which, like the C-terminal regions of all BRICHOS proteins except for proSP-C, has high β-sheet propensity (Fig. 2A). This might indicate that BRICHOS domains are present in precursor proteins in order to chaperone β-sheet prone regions and prevent aggregation. Provided that a similar binding and intramolecular chaperoning function also applies to BRICHOS domains from other families, the β-sheet prone stretches in the C-terminal region appear to be strong candidates for being physiological targets (Fig. 2A). These regions are well conserved in their respective families and are strongly predicted to form β-sheets [2]. For the proSP-C TM region and the ABri or ADan peptides, experimental data show that they actually form amyloid fibrils, but the predicted β-sheet prone regions for the other proteins have not been studied regarding their ability to form fibrils. It was recently observed that the non-polar residues Val, Ile, Phe and Cys (VIFC from their one-letter abbreviations) are highly prone to form β-sheets whereas the non-polar residues Leu, Ala and Met (LAM) prefer to form α-helices, and that amyloidogenic regions in proteins associated with amyloid disease appear to be overrepresented for VIFC but underrepresented for LAM [90]. Most of the C-terminal β-sheet prone regions in BRICHOS containing proteins, like the TM region of proSP-C, are VIFC biased (Fig. 2A), suggesting that they are able to form amyloid fibrils.

The ability of recombinant BRICHOS domains from Bri2 and proSP-C to bind amyloidogenic peptides in vitro goes beyond their supposed target peptides. Both these BRICHOS domains interact with Aβ40, and proSP-C BRICHOS also affects fibril formation of medin [57,89]. These data suggest that the BRICHOS domain can act also against non-target peptides, in contrast to the situation for pro-sequence-assisted protein folding that is highly specific for the respective substrate [91]. The binding to both Aβ and medin suggests that these amyloidogenic peptides can adopt similar conformations to BRICHOS target peptides. There are no obvious similarities in amino acid sequences among these peptides, but it is notable that they all contain at least two predicted β-strands. The NMR structure of the C-terminal part of arenicin and that of TFF1 (which binds GKN2, see above) show that both proteins contain regions that form strand–loop–strand conformations (Fig. 2B,C) [4,5,92]. It appears reasonable that these β-hairpins take part in binding interactions with the BRICHOS domain, and that predicted β-hairpins in the C-terminal regions (Fig 2) also bind to BRICHOS. These suggestions should be experimentally tested. Moreover, it was recently shown that Aβ can form a strand–loop–strand structure, which was required for formation of cytotoxic oligomers and fibrils [93,94]. Taken together, these observations suggest that BRICHOS binds a common intermediate motif in amyloid formation, a possibility that may be harnessed in future attempts to treat amyloid diseases.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References

The BRICHOS domain is present in a wide variety of disease-associated proteins that contain a region with high β-sheet propensity that is probably proteolytically released. Experimental findings hitherto indicate that the BRICHOS domain is an intramolecular chaperone domain that can bind β-hairpin motifs and prevent them from forming amyloid. This suggests that amyloid formation is a potential threat for many more proteins than so far recognized and that the BRICHOS domain might be harnessed in therapeutic strategies against amyloid diseases.


  1. Top of page
  2. Abstract
  3. Introduction
  4. proSP-C
  5. Bri2
  6. Proposed functions of the BRICHOS domain in different proteins
  7. Anti-amyloid activity of proSP-C and Bri2 BRICHOS
  8. Ability of BRICHOS to bind β-hairpin regions and implications for its function
  9. Concluding remarks
  10. Acknowledgements
  11. References
  • 1
    Sanchez-Pulido L, Devos D & Valencia A (2002) BRICHOS: a conserved domain in proteins associated with dementia, respiratory distress and cancer. Trends Biochem Sci 27, 329332.
  • 2
    Hedlund J, Johansson J & Persson B (2009) BRICHOS – a superfamily of multidomain proteins with diverse functions. BMC Res Notes 2, 180.
  • 3
    Westley BR, Griffin SM & May FE (2005) Interaction between TFF1, a gastric tumor suppressor trefoil protein, and TFIZ1, a BRICHOS domain-containing protein with homology to SP-C. Biochemistry 44, 79677975.
  • 4
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