Original Article Proteomic analysis of 14-3-3 zeta binding proteins in the mouse hippocampus

Introduction 14-3-3 proteinsare a family of conserved acidic proteins of which there are seven different iso-forms found in mammals (ζ, γ, η, e, β, θ, σ) [1]. They function as molecular adapters which in-teract with key signaling molecules and thereby regulate various cell functions including me-tabolism, division, differentiation, autophagy and apoptosis [2-4]. 14-3-3 proteinsare ubiqui-tously expressed, but are most abundant in the brain [5]. They are generally considered to be cytosolic proteins, although subcellular frac-tionation analyses of rat brain has shown they are also present in other compartments, includ-ing intracellular organelles such as mitochon-dria and the endoplasmic reticulum [6-8]. Knockout of 14-3-3 isoforms has demonstrated essential roles for some while loss of others appears to be adequately compensated by the remaining isoforms [9]. 14-3-3 proteinshave three main modes of ac-tion; altering conformation of their targets, physically occluding structural features, and scaffolding [9]. By doing so, 14-3-3 proteinsinfluence the functions of their targets, includ-ing modulating intracellular trafficking, blocking or activating enzymatic activity and influencing posttranslational modification. The identifica-tion of two binding motifs (RSXpSXP and RXY/FXpSP, where p denotes a phosphorylated ser-ine and X denotes any amino acid) [10] pro-vided critical insight into the mechanism of their binding, although many target proteinsdo not contain these motifs [9]. The advent of proteo-mic profiling has facilitated a large increase in the identification of 14-3-3 target proteinsand to date over 200 different binding partners have been identified [11-15]. These include protein kinases, phosphatases, signaling molecules, adaptors/scaffolding, transcription factors, re-ceptors and cytoskeletal proteins. Aberrant expression or function of 14-3-3 pro-teins has been linked to several diseases in-cluding cancer [16] and neurodegeneration [5]. Particular interest has emerged on 14-3-3ζ Int J Physiol Pathophysiol Pharmacol 2012;4(2):74-83 www.ijppp.org /ISSN:1944-8171/IJPPP1206001