5lfn | pdb_00005lfn
Crystal structure of human chondroadherin
Structural highlights
FunctionCHAD_HUMAN Promotes attachment of chondrocytes, fibroblasts, and osteoblasts. This binding is mediated (at least for chondrocytes and fibroblasts) by the integrin alpha(2)beta(1). May play an important role in the regulation of chondrocyte growth and proliferation (By similarity). Publication Abstract from PubMedChondroadherin (CHAD) is a cartilage matrix protein that mediates the adhesion of isolated chondrocytes. Its protein core is composed of 11 leucine-rich repeats (LRR) flanked by cysteine-rich domains. CHAD makes important interactions with collagen as well as with cell-surface heparin sulfate proteoglycans and alpha2beta1 integrins. The integrin-binding site is located in a region of hitherto unknown structure at the C-terminal end of CHAD. Peptides based on the C-terminal human CHAD (hCHAD) sequence have shown therapeutic potential for treating osteoporosis. This article describes a still-unconventional structure solution by phasing with de novo models, the first of a beta-rich protein. Structure determination of hCHAD using traditional, though nonsystematic, molecular replacement was unsuccessful in the hands of the authors, possibly owing to a combination of low sequence identity to other LRR proteins, four copies in the asymmetric unit and weak translational pseudosymmetry. However, it was possible to solve the structure by generating a large number of de novo models for the central LRR domain using Rosetta and multiple parallel molecular-replacement attempts using AMPLE. The hCHAD structure reveals an ordered C-terminal domain belonging to the LRRCT fold, with the integrin-binding motif (WLEAK) being part of a regular alpha-helix, and suggests ways in which experimental therapeutic peptides can be improved. The crystal structure itself and docking simulations further support that hCHAD dimers form in a similar manner to other matrix LRR proteins. Crystal structure of human chondroadherin: solving a difficult molecular-replacement problem using de novo models.,Ramisch S, Pramhed A, Tillgren V, Aspberg A, Logan DT Acta Crystallogr D Struct Biol. 2017 Jan 1;73(Pt 1):53-63. doi:, 10.1107/S205979831601980X. Epub 2017 Jan 1. PMID:28045385[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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