GPRASP/ARMCX protein family: potential involvement in health and diseases revealed by their novel interacting partners.
Fiche publication
Date publication
décembre 2020
Journal
Current topics in medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr SIMONIN Frédéric
Tous les auteurs :
Kaeffer J, Zeder-Lutz G, Simonin F, Lecat S
Lien Pubmed
Résumé
GPRASP (GPCR-associated sorting protein)/ARMCX (ARMadillo repeat-Containing proteins on the X chromosome) family is composed of 10 proteins, which genes are located on a small locus of the X chromosome except one. They possess at least two armadillo-like repeats on their carboxyl-terminal homologous sequence, but they can be subdivided on specific sequence features. Subfamily 1 (GPRASP1, GPRASP2, GPRASP3, ARMCX4 and ARMCX5) displays additional repeated motifs while a mitochondrial targeting transmembrane domain is present in subfamily 2 (ARMC10, ARMCX1, ARMCX2, ARMCX3 and ARMCX6). Although their roles are not yet fully understood, the recent identification of several interacting partners have shed new light on the processes in which GPRASP/ARMCX proteins are implicated. Among the interacting partners of proteins from subfamily 1, many are GPCRs. GPRASP1 binds trafficking proteins such as Beclin2 and the Dysbindin-HRS-Gas complex to participate in GPCR post-endocytic sorting. Moreover, in vitro as well as in vivo experiments indicate that GPRASP1 is a critical player in the adaptive responses related to chronic treatments with GPCR agonists. GPRASP2 seems to play a key role in the signalling of the hedgehog pathway in the primary cilium through a Smoothened-GPRASP2-Pifo complex. Identified small compound inhibitors of this complex could treat drug-resistant Smoothened derived cancer forms. Deletion of GPRASP2 in mice causes neurodevelopmental alteration and affects mGluR5 regulation, reflected by autism-like behaviour. Several members of subfamily 2, in complex with TRAK2 and MIRO, are involved in the trafficking of mitochondria in axons and on the regulation of their size and division, influencing the cell cycle. The essential role of GPRASP/ARMCX proteins in the cellular physiology is supported by human cases of deletions, causing male neonatal lethality by pulmonary delayed development, dysmorphic face and psychiatric and intellectual impacts in females.
Mots clés
Ciliopathies, Membrane Trafficking, Mitochondria Dynamics, Neurite Outgrowth, Pharmacology, Signalling, α-Solenoid Scaffolding Proteins
Référence
Curr Top Med Chem. 2020 Dec 1;: