Cannabinoid receptor interacting protein 1a interacts with myristoylated Gα i N terminus via a unique gapped β-barrel structure.

Autor: Booth WT; Department of Biochemistry and Center for Structural Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Clodfelter JE; Department of Biochemistry and Center for Structural Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Leone-Kabler S; Department of Physiology and Pharmacology and Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Hughes EK; Department of Biochemistry and Center for Structural Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; Department of Physiology and Pharmacology and Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Eldeeb K; Department of Physiology and Pharmacology and Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA., Howlett AC; Department of Physiology and Pharmacology and Center for Research on Substance Use and Addiction, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; Center for Molecular Signaling, Wake Forest University, Winston-Salem, North Carolina, USA. Electronic address: ahowlett@wakehealth.edu., Lowther WT; Department of Biochemistry and Center for Structural Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; Center for Molecular Signaling, Wake Forest University, Winston-Salem, North Carolina, USA. Electronic address: tlowther@wakehealth.edu.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2021 Sep; Vol. 297 (3), pp. 101099. Date of Electronic Publication: 2021 Aug 19.
DOI: 10.1016/j.jbc.2021.101099
Abstrakt: Cannabinoid receptor interacting protein 1a (CRIP1a) modulates CB 1 cannabinoid receptor G-protein coupling in part by altering the selectivity for Gα i subtype activation, but the molecular basis for this function of CRIP1a is not known. We report herein the first structure of CRIP1a at a resolution of 1.55 Å. CRIP1a exhibits a 10-stranded and antiparallel β-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 β-barrel has a gap between strands β8 and β10, which deviates from β-sandwich fatty acid-binding proteins that carry endocannabinoid compounds and the Rho-guanine nucleotide dissociation inhibitor predicted by computational threading algorithms. The structural homology search program DALI identified CRIP1a as homologous to a family of lipidated-protein carriers that includes phosphodiesterase 6 delta subunit and Unc119. Comparison with these proteins suggests that CRIP1a may carry two possible types of cargo: either (i) like phosphodiesterase 6 delta subunit, cargo with a farnesyl moiety that enters from the top of the β-barrel to occupy the hydrophobic interior or (ii) like Unc119, cargo with a palmitoyl or a myristoyl moiety that enters from the side where the missing β-strand creates an opening to the hydrophobic pocket. Fluorescence polarization analysis demonstrated CRIP1a binding of an N-terminally myristoylated 9-mer peptide mimicking the Gα i N terminus. However, CRIP1a could not bind the nonmyristolyated Gα i peptide or cargo of homologs. Thus, binding of CRIP1a to Gαi proteins represents a novel mechanism to regulate cell signaling initiated by the CB 1 receptor.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: