RACK1, A multifaceted scaffolding protein: Structure and function
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REVIEW
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RACK1, A multifaceted scaffolding protein: Structure and function David R Adams1, Dorit Ron2 and Patrick A Kiely3*
Abstract The Receptor for Activated C Kinase 1 (RACK1) is a member of the tryptophan-aspartate repeat (WD-repeat) family of proteins and shares significant homology to the b subunit of G-proteins (Gb). RACK1 adopts a seven-bladed bpropeller structure which facilitates protein binding. RACK1 has a significant role to play in shuttling proteins around the cell, anchoring proteins at particular locations and in stabilising protein activity. It interacts with the ribosomal machinery, with several cell surface receptors and with proteins in the nucleus. As a result, RACK1 is a key mediator of various pathways and contributes to numerous aspects of cellular function. Here, we discuss RACK1 gene and structure and its role in specific signaling pathways, and address how posttranslational modifications facilitate subcellular location and translocation of RACK1. This review condenses several recent studies suggesting a role for RACK1 in physiological processes such as development, cell migration, central nervous system (CN) function and circadian rhythm as well as reviewing the role of RACK1 in disease. Keywords: RACK1, WD-repeat, guanine nucleotide binding protein 2-like 1, (Gβ), heterotrimeric G-proteins, PKCβII, scaffolding protein
Introduction The WD-repeat family of proteins
The tryptophan, aspartic acid repeat (WD-repeat containing proteins are an ancient conservative family of proteins found in prokaryotes and all eukaryotes [1]. They are involved in almost every signaling pathway and are associated with many genetic diseases. To date over 100 WD-repeat proteins have been assigned with an approved name and designation in the human nomenclature database. Genes encoding WD-repeat proteins are found on all chromosomes except 20, 22 (a pseudogene FBXW4P1 has been reported in chromosome 22), and the Y chromosome http://www.genenames.org This reflects their diversity and importance as a family, and suggests that their expression is regulated by a variety of signaling pathways. WD-repeats themselves are sequences of typically 44-60 amino acids in length ending at the C-terminus with a signature WD dipeptide or its equivalent (Figure 1). The motifs were first identified as repeating segments of homologous sequence within * Correspondence: [email protected] 3 Department of Life Sciences, and Materials and Surface Science Institute, University of Limerick, Limerick, Ireland Full list of author information is available at the end of the article
the primary structure of the transducin Gb subunit and CDC4 [2]. Detailed analysis with a larger cohort of proteins revealed that the repeats are also typified by a characteristic GH dipeptide usually residing some 11-24 residues from the N-terminus, though neither the GH nor WD signature is absolutely conserved [3-5]. Several other characteristic amino acids contribute to the repeat, most notably an aspartic acid located 6 residues before the WD di
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