The luteinizing hormone receptor (LHR) is one of eight members in a cluster of the rhodopsin family of the large G protein-coupled receptor (GPCR) superfamily that contains some 800-900 genes in the human genome. LHR, along with its paralogons, follicle stimulating hormone receptor (FSHR) and thyroid stimulating hormone receptor, form one of the three classes in this cluster; the two other classes contain the relaxin-binding GPCRs and orphan GPCRs. These GPCRs are characterized by a relatively large ectodomain (ECD) containing leucine-rich-repeats (LRRs); in the class of glycoprotein hormone receptors, the LRR region is capped by N-terminal and C-terminal cysteine-rich regions. Binding of human chorionic gonadotropin (hCG) or luteinizing hormone to the LHR-ECD triggers a conformational change of the transmembrane region of the receptor facilitating binding and activation of Gs, followed by effector enzyme activation and subsequent intracellular signaling. Viewing LHR as a transmembrane anchoring protein that sequentially binds hCG and Gs to give the hCG-LHR-Gs complex, numerous interactions and conformational changes must be considered. There is, unfortunately, a paucity of structural data on LHR, but crystal structures exist for hCG, the homologous FSH-FSHR-ECD (N-terminal fragment) complex, rhodopsin (in the inactive state), an active form of Galphas (transducin), and the betagamma heterodimer. Using a combined experimental (site-directed mutagenesis followed by characterization in transfected cells) and computational (homology modeling and molecular dynamics simulations) approach, good working models are being developed for the protein-protein interaction faces and, in some cases, the ensuing conformational changes induced by complex formation. hCG binding to the LHR-ECD appears to involve several LRRs; LHR activation can be described in terms of disrupting a network of H-bonds in the cytosolic halves of helices 1-3, 6, and 7; and binding of LHR to Gs involves, in large part, intracellular loop 2 binding, presumably to Gsalpha at its C-terminus. Major gaps exist in our understanding at the molecular level of the six-polypeptide chain complex, hCG-LHR-Gs, but considerable progress has been made in the past few years.
A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein / Puett, D; Li, Y; Demars, G; Angelova, K; Fanelli, Francesca. - In: MOLECULAR AND CELLULAR ENDOCRINOLOGY. - ISSN 0303-7207. - ELETTRONICO. - 260-262(2007), pp. 126-136. [10.1016/j.mce.2006.05.009]
|Data di pubblicazione:||2007|
|Titolo:||A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein|
|Autore/i:||Puett, D; Li, Y; Demars, G; Angelova, K; Fanelli, Francesca|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.mce.2006.05.009|
|Codice identificativo ISI:||WOS:000243202300016|
|Codice identificativo Scopus:||2-s2.0-33751331631|
|Codice identificativo Pubmed:||17059864|
|Citazione:||A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein / Puett, D; Li, Y; Demars, G; Angelova, K; Fanelli, Francesca. - In: MOLECULAR AND CELLULAR ENDOCRINOLOGY. - ISSN 0303-7207. - ELETTRONICO. - 260-262(2007), pp. 126-136. [10.1016/j.mce.2006.05.009]|
|Tipologia||Articolo su rivista|
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