Identification and Analysis of a Novel Dimerization Domain Shared by Various Members of c-Jun N-terminal Kinase (JNK) Scaffold Proteins

Abstract

Background: WDR62 is a JNK scaffold protein. Results:We identified at the WDR62 C terminus a loop-helix domain that is responsible for its homodimerization and association with another JNK scaffold protein, MAPKBP1. WDR62 dimerization is required for JNK and MKK7␤1 recruitment. Conclusion: WDR62 dimerization is required for its scaffolding function. Significance: Scaffold protein association offers another layer of complexity for the fine tuning of signaling pathways.

Molecular evolution of WDR62, a gene that regulates neocorticogenesis

“…Loop helix (LH) domain is located at the carboxyl terminus of human WDR62 (1414–1520) and it is necessary for homodimerization ( Cohen-Katsenelson et al, 2013 ). LH domain is present across all orthologous copies analyzed.…”

“…Domains were allocated to human WDR62 as previously described ( Cohen-Katsenelson et al, 2011 , Cohen-Katsenelson et al, 2013 ). Furthermore, novel domains along human WDR62 (which were not previously known) were predicted by SMART database and MyHits tool ( Schultz et al, 1998 , Pagni et al, 2004 ).…”

“…Furthermore, WDR62 does not share definite sequence homology especially at the C-terminus to any known protein ( Nicholas et al, 2010 ). Recent molecular data revealed the interaction of WDR62 protein with multiple other proteins including JNK, MKK7β1, MAPKBP1 and also with centrosomal protein CEP170 ( Yu et al, 2010 , Cohen-Katsenelson et al, 2011 , Cohen-Katsenelson et al, 2013 ). Expression study of human and mouse embryonic brain implies that WDR62 is highly expressed in the forebrain particularly in ventricular and sub-ventricular zone during the neurogenesis of cerebral cortex ( Bilguvar et al, 2010 , Nicholas et al, 2010 ).…”

Novel nephronophthisis-associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment

“…However, its physiological role largely remains unknown and only a small number of studies focused on detailed functional aspects. [5][6][7][8] However, its JNK-binding paralog WDR62, a microcephaly-associated protein (MIM# 604317), 9 was intensively studied and found to be recruited to specialized granular cell compartments upon stress induction together with MAPKBP1. 7,10 MAPKBP1 was speculated to play a role in cell cycle regulation, as mutant variants unlike the wild type (WT) were not able to colocalize with WDR62 at mitotic spindle poles (MSPs).…”

A novel single base pair duplication in WDR62 causes primary microcephaly

“…It encodes for a 1523 amino acid long protein that comprises 15 WD-40 repeats, one CpG signal and a polyadenylation signal [ 13 , 19 , 24 - 26 ]. The homodimerization region can be found on the C-terminal domain which shows no sequence homologies to any known oligomerization signals [ 27 ]. First studies on WDR62 revealed it as a JNK scaffold protein that associates with the two JNK-signalling pathway proteins JNK (c-Jun N-terminal kinase) and MKK7 (MAP kinase kinase 7) and is recruited to stress granulaes upon cellular stress induction [ 28 ].…”