TY - JOUR
T1 - Structure of the RECK CC domain, an evolutionary anomaly
AU - Chang, Tao Hsin
AU - Hsieh, Fu Lien
AU - Smallwood, Philip M.
AU - Gabelli, Sandra B.
AU - Nathans, Jeremy
N1 - Funding Information:
ACKNOWLEDGMENTS. The authors thank Jean Jakoncic and Alexei Soares at the 17-ID-1 AMX beamline (Brookhaven National Laboratory) for assistance with data collection; Luca Jovine (Karolinska Institute) for the pHLmMBP vector; Ray Owens (Protein Production UK) and David Drew (Stockholm University) for helpful discussions about in-gel fluorescent imaging; and Chris Cho, Amir Rattner, and Jie Wang for advice and/or helpful comments on the manuscript. This work was supported by the Howard Hughes Medical Institute, the National Eye Institute (NIH; Grant R01EY018637), and the Arnold and Mabel Beckman Foundation. T.-H.C. was supported by a Human Frontier Science Program long-term fellowship (Grant LT000130/2017-L). S.B.G. was supported by Department of Defense Congressionally Directed Medical Research Programs Grant BC151831 and the National Cancer Institute (NIH) Grant CA062924SBG. Work at the Center for Biomolecular Structure beamline AMX (17ID-1) | FMX (17ID-2) | LIX (16ID) at NSLS-II was supported by the National Institute of General Medical Sciences (NIH; Grant 1P30GM133893), the Office of Biological and Environmental Research (Department of Energy [DOE]; Grant BER-BO 070), and the Office of Basic Energy Sciences Program (DOE; Grant BES-FWP-PS001).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/6/30
Y1 - 2020/6/30
N2 - Five small protein domains, the CC-domains, at the N terminus of the RECK protein, play essential roles in signaling by WNT7A and WNT7B in the context of central nervous system angiogenesis and blood-brain barrier formation and maintenance. We have determined the structure of CC domain 4 (CC4) at 1.65-A resolution and find that it folds into a compact four-helix bundle with three disulfide bonds. The CC4 structure, together with homology modeling of CC1, reveals the surface locations of critical residues that were shown in previous mutagenesis studies to mediate GPR124 binding and WNT7A/WNT7B recognition and signaling. Surprisingly, sequence and structural homology searches reveal no other cellsurface or secreted domains in vertebrates that resemble the CC domain, a pattern that is in striking contrast to other ancient and similarly sized domains, such as Epidermal Growth Factor, Fibronectin Type 3, Immunoglobulin, and Thrombospondin type 1 domains, which are collectively present in hundreds of proteins.
AB - Five small protein domains, the CC-domains, at the N terminus of the RECK protein, play essential roles in signaling by WNT7A and WNT7B in the context of central nervous system angiogenesis and blood-brain barrier formation and maintenance. We have determined the structure of CC domain 4 (CC4) at 1.65-A resolution and find that it folds into a compact four-helix bundle with three disulfide bonds. The CC4 structure, together with homology modeling of CC1, reveals the surface locations of critical residues that were shown in previous mutagenesis studies to mediate GPR124 binding and WNT7A/WNT7B recognition and signaling. Surprisingly, sequence and structural homology searches reveal no other cellsurface or secreted domains in vertebrates that resemble the CC domain, a pattern that is in striking contrast to other ancient and similarly sized domains, such as Epidermal Growth Factor, Fibronectin Type 3, Immunoglobulin, and Thrombospondin type 1 domains, which are collectively present in hundreds of proteins.
KW - Blood-brain barrier
KW - Extracellular domain
KW - Four-helix bundle
KW - Protein evolution
KW - Wnt signaling
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U2 - 10.1073/pnas.2006332117
DO - 10.1073/pnas.2006332117
M3 - Article
C2 - 32541044
AN - SCOPUS:85087465843
SN - 0027-8424
VL - 117
SP - 15104
EP - 15111
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -