Not Just Another Scaffolding Protein Family: The Multifaceted MPPs

Abstract

Membrane palmitoylated proteins (MPPs) are a subfamily of a larger group of multidomain proteins, namely, membrane-associated guanylate kinases (MAGUKs). The ubiquitous expression and multidomain structure of MPPs provide the ability to form diverse protein complexes at the cell membranes, which are involved in a wide range of cellular processes, including establishing the proper cell structure, polarity and cell adhesion. The formation of MPP-dependent complexes in various cell types seems to be based on similar principles, but involves members of different protein groups, such as 4.1-ezrin-radixin-moesin (FERM) domain-containing proteins, polarity proteins or other MAGUKs, showing their multifaceted nature. In this review, we discuss the function of the MPP family in the formation of multiple protein complexes. Notably, we depict their significant role for cell physiology, as the loss of interactions between proteins involved in the complex has a variety of negative consequences. Moreover, based on recent studies concerning the mechanism of membrane raft formation, we shed new light on a possible role played by MPPs in lateral membrane organization.

Keywords: cell adhesion; cell polarity; membrane palmitoylated protein (MPP); membrane rafts; membrane-associated guanylate kinases (MAGUKs).

Figure 1

Structural features of membrane palmitoylated proteins (MPPs). (a) Schematic representation of domain structure of MPPs. The boundaries of the three canonical domains (cylinders) were estimated according to the UniProt database (www.uniprot.org). (b) Model of three-dimensional structure of MPP1 built with the I-TASSER web server [43]. Color code corresponds to the domains depicted in (a). Examples of complexes formed by MPPs with their partner proteins/protein fragments (in yellow); (c) the PDZ domain of MPP1 in complex with glycophorin C-terminal peptide (PDB ID: 2EJY) [44]; (d) the MPP5 PDZ/SH3/GUK tandem (for explanation of these abbreviations see the main text) bound to CRB–cytoplasmic tail (CT) (PDB ID: 4WSI) [25]; (e) the MPP5 L27N and Pals1-associated tight junction protein (PATJ) L27 heterodimer complex (PDB ID: 1VF6) [45].

Figure 2

MPPs in protein complexes. Schematic illustration of protein complexes formed by MPPs. (a) Scaffolding ternary complex formed by MPP1, glycophorin C (GPC) and protein 4.1 found in erythrocyte membranes; (b) scaffolding complex formed by MPP2, postsynaptic density protein 95 (PSD-95), guanylate kinase-associated protein (GKAP) and CADM1 found at neuronal postsynaptic membrane; (c) Crumbs polarity complex formed by MPP5, CRB and PATJ and partitioning defective (Par) complex formed by Par6, Par3 and atypical protein kinase C (aPKC) found in epithelial cells. See main text for details.

Figure 3

Proposed mechanism of functional membrane raft formation. Palmitoylated MPP1 binds to the flotillins present in cholesterol and sphingomyelin-enriched nano-assemblies. This binding initiates oligomerization of flotillins and coalescence of nano-assemblies into membrane rafts.