Structure of human peptidyl-prolyl cis–trans isomerase FKBP22 containing two EF-hand motifs

Authors

  • Sergei P. Boudko,

    1. Research Department, Shriners Hospital for Children, Portland, Oregon
    2. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon
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  • Yoshihiro Ishikawa,

    1. Research Department, Shriners Hospital for Children, Portland, Oregon
    2. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon
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  • Jay Nix,

    1. Molecular Biology Consortium, Advanced Light Source Beamline, Lawrence Berkeley National Laboratory, Berkeley, California
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  • Michael S. Chapman,

    1. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon
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  • Hans Peter Bächinger

    Corresponding author
    1. Research Department, Shriners Hospital for Children, Portland, Oregon
    2. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon
    • Correspondence to: Hans Peter Bächinger, Research Department, Shriners Hospital for Children, 3101 SW Sam Jackson Park Road, Portland, OR 97239. E-mail: hpb@shcc.org

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Abstract

The FK506-binding protein (FKBP) family consists of proteins with a variety of protein–protein interaction domains and versatile cellular functions. It is assumed that all members are peptidyl-prolyl cis–trans isomerases with the enzymatic function attributed to the FKBP domain. Six members of this family localize to the mammalian endoplasmic reticulum (ER). Four of them, FKBP22 (encoded by the FKBP14 gene), FKBP23 (FKBP7), FKBP60 (FKBP9), and FKBP65 (FKBP10), are unique among all FKBPs as they contain the EF-hand motifs. Little is known about the biological roles of these proteins, but emerging genetics studies are attracting great interest to the ER resident FKBPs, as mutations in genes encoding FKBP10 and FKBP14 were shown to cause a variety of matrix disorders. Although the structural organization of the FKBP-type domain as well as of the EF-hand motif has been known for a while, it is difficult to conclude how these structures are combined and how it affects the protein functionality. We have determined a unique 1.9 Å resolution crystal structure for human FKBP22, which can serve as a prototype for other EF hand-containing FKBPs. The EF-hand motifs of two FKBP22 molecules form a dimeric complex with an elongated and predominantly hydrophobic cavity that can potentially be occupied by an aliphatic ligand. The FKBP-type domains are separated by a cleft and their putative active sites can catalyze isomerazation of two bonds within a polypeptide chain in extended conformation. These structural results are of prime interest for understanding biological functions of ER resident FKBPs containing EF-hand motifs.

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