Molecular evolution of the MAGUK family in metazoan genomes

Velthuis, Aartjan J.W. te; Admiraal, Jeroen; Bagowski, Christoph P.

doi:10.1186/1471-2148-7-129

Cited by 66 publications

(86 citation statements)

References 45 publications

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“…We confirmed that the mutation induces spindle orientation activity in an extant fungal GK enz (S35P; Saccharomyces enzyme numbering), a lineage that lacks MAGUKs [ Fig. 2A; (4,6)]. Thus, a single mutation is sufficient for the functional evolution of a nucleotide kinase to a spindle-orienting domain within the GK protein fold.…”

Section: Resultssupporting

confidence: 58%

Conversion of the enzyme guanylate kinase into a mitotic-spindle orienting protein by a single mutation that inhibits GMP-induced closing

Johnston

Whitney

Volkman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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New protein functions can require complex sequence changes, but the minimal path is not well understood. The guanylate kinase enzyme (GK enz ), which catalyzes phosphotransfer from ATP to GMP, evolved into the GK domain (GK dom ), a protein-binding domain found in membrane associate guanylate kinases that function in mitotic spindle orientation and cell adhesion. Using an induced polarity assay for GK dom function, we show that a single serine to proline mutation is sufficient to switch extant GK enz into a functional GK dom . The mutation blocks catalysis (GK enz function) but allows protein binding and spindle orientation (GK dom function). Furthermore, whereas the GK enz undergoes a large closing motion upon GMP binding, fluorescence quenching and NMR demonstrate that the S → P mutation inhibits GMP-induced GK movements. Disrupting GK closing with a mutation at a different position also leads to GK dom function, suggesting that blocking the GK enz closing motion is sufficient for functional conversion of GK enz to GK dom . Although subtle changes in protein function can require complex sequence paths, our work shows that entirely new functions can arise from single mutations that alter protein dynamics.protein interactions | neofunctionalization | protein engineering | molecular evolution P roteins perform remarkably diverse functions including catalysis, small molecule binding, and protein recognition. Molecular evolution seeks to understand how the diversity of known protein functions arose, whereas the goal of protein engineering is to create new ones (1). An evolutionary process for creating new protein functions is the divergent evolution of duplicated genes, in which gene duplication is followed by functional evolution [neofunctionalization; (2)]. However, loss of function (pseudogene formation or nonfunctionalization) competes with functional evolution and may be much more likely (3). The degree to which neofunctionalization can "win out" over pseudogene formation depends on the number of mutations required to attain the new function and the possible paths in sequence space to the new function. Thus, neofunctionalization is a competitive process that is dependent on the number of required mutations and how protein function is achieved. Insight into the mechanisms of neofunctionalization should improve our ability to develop previously undescribed protein functions.We examined neofunctionalization in the context of a dramatic functional change: creation of a mitotic spindle-orienting protein from a nucleotide kinase within the membrane associated guanylate kinase (MAGUK) family of proteins. MAGUKs are proteins that mediate intricate multicellular functions such as cell junction formation and mitotic spindle orientation and have been found only in metazoans and choanoflagellates (4, 5).

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Section: Resultssupporting

confidence: 58%

Conversion of the enzyme guanylate kinase into a mitotic-spindle orienting protein by a single mutation that inhibits GMP-induced closing

Johnston

Whitney

Volkman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Structural and molecular studies have shown that PDZ domains are pivotal features of scaffolding proteins and localize MAGUKs and their interaction partners to specialized membrane domains of neuronal and epithelial cells (10,11). The domain architecture of the MAGUKs enables interaction with receptors, the actin cytoskeleton, and ion channels but also allows the tethering together of different MAGUK subfamily proteins (50), which may contain up to six PDZ domains (44).…”

Section: Discussionmentioning

confidence: 99%

EspF Interacts with Nucleation-Promoting Factors To Recruit Junctional Proteins into Pedestals for Pedestal Maturation and Disruption of Paracellular Permeability

Peralta-Ramirez¹,

Hernández²,

Manning‐Cela

et al. 2008

Infect Immun

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Many pathogenic bacteria subvert normal host cell processes by delivering effector proteins which mimic eukaryotic functions directly into target cells. EspF is a multifunctional protein injected into host cells by attaching and effacing pathogens, but its mechanism of action is not understood completely. In silico analyses of EspF revealed two key motifs: proline-rich domains and PDZ domain binding motifs. Such functional domains may allow EspF to act as an actin nucleation-promoting factor by mimicking host proteins. In agreement with these predictions, we found that EspF from rabbit enteropathogenic Escherichia coli (E22) participates in the regulation of actin polymerization by binding to a complex of proteins at the tight junctions (TJ). EspF bound to actin and profilin throughout the course of infection. However, after 2 h of infection, EspF also bound to the neural Wiskott-Aldrich syndrome protein and to the Arp2/3, zonula occludens-1 (ZO-1), and ZO-2 proteins. Moreover, EspF caused occludin, claudin, ZO-1, and ZO-2 redistribution and loss of transepithelial electrical resistance, suggesting that actin sequestration by EspF may cause local actin depolymerization leading to EspF-induced TJ disruption. Furthermore, EspF caused recruitment of these TJ proteins into the pedestals. An E22 strain lacking EspF did not cause TJ disruption and pedestals were smaller than those induced by the wild-type strain. Additionally, the pedestals were located mainly in the TJ. The overexpression of EspF caused bigger pedestals located along the length of the cells. Thus, actin sequestration by EspF allows the recruitment of junctional proteins into the pedestals, leading to the maturation of actin pedestals and the disruption of paracellular permeability.

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“…Ca 21 /calcium/calmodulin-dependent serine protein kinase (CASK) is very similar in topology to the MPPs, with protein domains that include a catalytically active Ca 21 /calmodulindependent kinase domain at the amino-terminus followed by two L27 domains, a PDZ domain, an SH3 domain, and a GK domain (te Velthuis et al, 2007;Mukherjee et al, 2008) (Fig. 1).…”

Section: Containing Maguk Proteinsmentioning

confidence: 99%

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Dunn

Ferguson

2015

Mol Pharmacol

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G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins, postsynaptic density protein of 95 kilodaltons, disc large, zona occludens-1 (PDZ) domain-containing proteins appear most abundant and have similarly been implicated in disease mechanisms. PDZ proteins play an important role in regulating receptor and channel protein localization within synapses and tight junctions and function to scaffold intracellular signaling protein complexes. In the current study, we review the known functional interactions between PDZ domain-containing proteins and GPCRs and provide insight into the potential mechanisms of action. These PDZ domain-containing proteins include the membraneassociated guanylate-like kinases [postsynaptic density protein of 95 kilodaltons; synapse-associated protein of 97 kilodaltons; postsynaptic density protein of 93 kilodaltons; synapse-associated protein of 102 kilodaltons; discs, large homolog 5; caspase activation and recruitment domain and membrane-associated guanylate-like kinase domain-containing protein 3; membrane protein, palmitoylated 3; calcium/calmodulin-dependent serine protein kinase; membrane-associated guanylate kinase protein (MAGI)-1, MAGI-2, and MAGI-3], Na 1 /H 1 exchanger regulatory factor proteins (NHERFs) (NHERF1, NHERF2, PDZ domaincontaining kidney protein 1, and PDZ domain-containing kidney protein 2), Golgi-associated PDZ proteins (Ga-binding protein interacting protein, C-terminus and CFTR-associated ligand), PDZ domain-containing guanine nucleotide exchange factors (GEFs) 1 and 2, regulator of G protein signaling (RGS)-homology-RhoGEFs (PDZ domain-containing RhoGEF and leukemia-associated RhoGEF), RGS3 and RGS12, spinophilin and neurabin-1, SRC homology 3 domain and multiple ankyrin repeat domain (Shank) proteins (Shank1, Shank2, and Shank3), partitioning defective proteins 3 and 6, multiple PDZ protein 1, Tamalin, neuronal nitric oxide synthase, syntrophins, protein interacting with protein kinase C a 1, syntenin-1, and sorting nexin 27.

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Molecular evolution of the MAGUK family in metazoan genomes

Cited by 66 publications

References 45 publications

Conversion of the enzyme guanylate kinase into a mitotic-spindle orienting protein by a single mutation that inhibits GMP-induced closing

Conversion of the enzyme guanylate kinase into a mitotic-spindle orienting protein by a single mutation that inhibits GMP-induced closing

EspF Interacts with Nucleation-Promoting Factors To Recruit Junctional Proteins into Pedestals for Pedestal Maturation and Disruption of Paracellular Permeability

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

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