New hypotheses about the structure–function of proprotein convertase subtilisin/kexin type 9: Analysis of the epidermal growth factor-like repeat A docking site using WaterMap
Article first published online: 18 MAY 2010
Copyright © 2010 Wiley-Liss, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 78, Issue 12, pages 2571–2586, September 2010
How to Cite
Pearlstein, R. A., Hu, Q.-Y., Zhou, J., Yowe, D., Levell, J., Dale, B., Kaushik, V. K., Daniels, D., Hanrahan, S., Sherman, W. and Abel, R. (2010), New hypotheses about the structure–function of proprotein convertase subtilisin/kexin type 9: Analysis of the epidermal growth factor-like repeat A docking site using WaterMap. Proteins, 78: 2571–2586. doi: 10.1002/prot.22767
- Issue published online: 22 JUL 2010
- Article first published online: 18 MAY 2010
- Accepted manuscript online: 18 MAY 2010 12:00AM EST
- Manuscript Accepted: 28 APR 2010
- Manuscript Revised: 5 APR 2010
- Manuscript Received: 4 JAN 2010
- protein–protein interactions;
LDL cholesterol (LDL-C) is cleared from plasma via cellular uptake and internalization processes that are largely mediated by the low-density lipoprotein cholesterol receptor (LDL-R). LDL-R is targeted for lysosomal degradation by association with proprotein convertase subtilisin-kexin type 9 (PCSK9). Gain of function mutations in PCSK9 can result in excessive loss of receptors and dyslipidemia. On the other hand, receptor-sparing phenomena, including loss-of-function mutations or inhibition of PCSK9, can lead to enhanced clearance of plasma lipids. We hypothesize that desolvation and resolvation processes, in many cases, constitute rate-determining steps for protein–ligand association and dissociation, respectively. To test this hypothesis, we analyzed and compared the predicted desolvation properties of wild-type versus gain-of-function mutant Asp374Tyr PCSK9 using WaterMap, a new in silico method for predicting the preferred locations and thermodynamic properties of water solvating proteins (“hydration sites”). We compared these results with binding kinetics data for PCSK9, full-length LDL-R ectodomain, and isolated EGF-A repeat. We propose that the fast kon and entropically driven thermodynamics observed for PCSK9-EGF-A binding stem from the functional replacement of water occupying stable PCSK9 hydration sites (i.e., exchange of PCSK9 H-bonds from water to polar EGF-A groups). We further propose that the relatively fast koff observed for EGF-A unbinding stems from the limited displacement of solvent occupying unstable hydration sites. Conversely, the slower koff observed for EGF-A and LDL-R unbinding from Asp374Tyr PCSK9 stems from the destabilizing effects of this mutation on PCSK9 hydration sites, with a concomitant increase in the persistence of the bound complex. Proteins 2010. © 2010 Wiley-Liss, Inc.