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Publication Abstract from PubMed

Cannabinoid receptor interacting protein 1a (CRIP1a) modulates CB1 cannabinoid receptor G-protein coupling in part by altering the selectivity for Galphai subtype activation, but the molecular basis for this function of CRIP1a is not known. We report herein the first structure of CRIP1a at 1.55 A resolution. CRIP1a exhibits a 10-stranded, antiparallel beta-barrel with an interior comprised of conserved hydrophobic residues and loops at the bottom and a short helical cap at the top to exclude solvent. The beta-barrel has a gap between strands beta8 and beta10, which deviates from beta-sandwich fatty acid binding proteins that carry endocannabinoid compounds and the Rho-guanine nucleotide dissociation inhibitor (GDI) predicted by computational threading algorithms. The structural homology search program DALI identified CRIP1a as homologous to a family of lipidated-protein carriers that includes PDE6delta and Unc119. Comparison with these proteins suggests that CRIP1a may carry two possible types of cargo: either (i) like PDE6delta, cargo with a farnesyl moiety that enters from the top of the beta-barrel to occupy the hydrophobic interior, or (ii) like Unc119, cargo with a palmitoyl or myristoyl moiety that enters from the side where the missing beta-strand creates an opening to the hydrophobic pocket. Fluorescence polarization analysis demonstrated CRIP1a binding of an N-terminally myristoylated 9-mer peptide mimicking the Galphai N-terminus. However, CRIP1a could not bind the non-myristolyated Galphai peptide or cargo of homologs. Thus, binding of CRIP1a to Galphai proteins represents a novel mechanism to regulate cell signaling initiated by the CB1 receptor.

Cannabinoid receptor interacting protein 1a (CRIP1a) interacts with myristoylated Galphai-N-terminus via a unique gapped beta-barrel structure.,Booth WT, Clodfelter JE, Leone-Kabler S, Hughes EK, Eldeeb K, Howlett AC, Lowther WT J Biol Chem. 2021 Aug 18:101099. doi: 10.1016/j.jbc.2021.101099. PMID:34418434^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.