6byv | pdb_00006byv
Solution NMR structure of cysteine-rich calcium bound domains of very low density lipoprotein receptor
Structural highlights
Disease[VLDLR_HUMAN] Defects in VLDLR are the cause of cerebellar ataxia mental retardation and dysequilibrium syndrome type 1 (CMARQ1) [MIM:224050]; also known as dysequilibrium syndrome (DES) or non-progressive cerebellar disorder with mental retardation. CMARQ1 is a congenital, non-progressive cerebellar ataxia associated with disturbed equilibrium, delayed ambulation, mental retardation and cerebellar hypoplasia. Additional features include short stature, strabismus, pes planus and, rarely, seizures.[1] Function[VLDLR_HUMAN] Binds VLDL and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits. Binding to Reelin induces tyrosine phosphorylation of Dab1 and modulation of Tau phosphorylation (By similarity). Publication Abstract from PubMedOur previous studies revealed that interaction of fibrin with the very low density lipoprotein (VLDL) receptor plays a prominent role in transendothelial migration of leukocytes and thereby inflammation. The major goal of our subsequent studies is to establish the structural basis for this interaction. As the first step toward this goal, we localized the fibrin-binding sites within cysteine-rich (CR) domains 2-4 of the VLDL receptor. In this study, we have made a next step toward this goal by establishing the nuclear magnetic resonance solution structure of the recombinant VLDLR(2-4) fragment containing all three fibrin-binding CR domains of this receptor. The structure revealed that all three CR domains have a similar general fold. Each domain contains a calcium-binding loop, and the loop in the CR3 domain has a unique conformation relative to the other two. Domains CR2 and CR3 interact with each other, while CR4 is flexible relative to the other two domains. In addition, analysis of the electrostatic potential surface of VLDLR(2-4) revealed extended negatively charged regions in each of its CR domains. The presence of these regions suggests that they may interact with three positively charged clusters of the fibrin betaN domain whose involvement in interaction with the VLDL receptor was demonstrated earlier. Altogether, these findings provide a solid background for our next step toward establishing the structural basis for fibrin-VLDL receptor interaction. Nuclear Magnetic Resonance Solution Structure of the Recombinant Fragment Containing Three Fibrin-Binding Cysteine-Rich Domains of the Very Low Density Lipoprotein Receptor.,Banerjee K, Yakovlev S, Gruschus JM, Medved L, Tjandra N Biochemistry. 2018 Jul 17. doi: 10.1021/acs.biochem.8b00349. PMID:29965730[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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