SNARE phosphorylation: a control mechanism for insulin-stimulated glucose transport and other regulated exocytic events

Laidlaw, Kamilla M.E.; Livingstone, Rachel; Al-Tobi, Mohammed; Bryant, Nia J.; Gould, Gwyn W.

doi:10.1042/bst20170202

Cited by 16 publications

(14 citation statements)

References 48 publications

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“…Another role for ATP is in phosphorylation of protein substrates important for exocytosis. This topic is reviewed elsewhere in detail (Klenchin and Martin, 2000; Laidlaw et al, 2017; Kadkova et al, 2018).…”

Section: The Role Of Atp In Exocytosismentioning

confidence: 99%

Unraveling the mechanisms of calcium-dependent secretion

Anantharam

Kreutzberger

2019

Journal of General Physiology

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Ca2+-dependent secretion is a process by which important signaling molecules that are produced within a cell—including proteins and neurotransmitters—are expelled to the extracellular environment. The cellular mechanism that underlies secretion is referred to as exocytosis. Many years of work have revealed that exocytosis in neurons and neuroendocrine cells is tightly coupled to Ca2+ and orchestrated by a series of protein–protein/protein–lipid interactions. Here, we highlight landmark discoveries that have informed our current understanding of the process. We focus principally on reductionist studies performed using powerful model secretory systems and cell-free reconstitution assays. In recent years, molecular cloning and genetics have implicated the involvement of a sizeable number of proteins in exocytosis. We expect reductionist approaches will be central to attempts to resolve their roles. The Journal of General Physiology will continue to be an outlet for much of this work, befitting its tradition of publishing strongly mechanistic, basic research.

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Section: The Role Of Atp In Exocytosismentioning

confidence: 99%

Unraveling the mechanisms of calcium-dependent secretion

Anantharam

Kreutzberger

2019

Journal of General Physiology

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“…Posttranslational modifications of secretion machinery proteins are known as powerful ways to regulate exocytosis. In contrast to the well-characterized serine/threonine phosphorylation, the importance of tyrosine phosphorylation in exocytosis has only recently begun to be appreciated (Cijsouw et al, 2014;Gabel et al, 2019;Jewell et al, 2011;Laidlaw et al, 2017;Meijer et al, 2018;Seino et al, 2009). In addition to the phosphorylation of NSF at its pY 83 site, recent studies have shown that tyrosine phosphorylation of MUNC18-3 at the pY 219 and pY 527 sites, Annexin-A2 at pY 23 , and MUNC18-1 at pY 473 actively participates in the vesicle release machinery to explicitly regulate exocytosis processes (Gabel et al, 2019;Jewell et al, 2011;Meijer et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…There are three major exocytosis pathways in secretory cells, namely, full-collapse fusion, kiss-and-run, and compound exocytosis, which possess different secretion rates and release amount (Sudhof, 2004). It has previously been reported that the phosphorylation of critical proteins at serine/threonine or tyrosine residues participates in stimulus-secretion coupling in certain important exocytosis processes, for example, the secretion of insulin from pancreatic β cells and the secretion of catecholamine from the adrenal medulla (Laidlaw et al, 2017;Ortsater et al, 2014;Seino et al, 2009). However, the exact roles of protein tyrosine phosphatases (PTPs) in the regulation of key hormone secretion procedures are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates

Chen

Yang

et al. 2019

Preprint

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41The tyrosine phosphorylation of secretion machinery proteins is a crucial regulatory 42 mechanism for exocytosis. However, the participation of tyrosine phosphatases in 43 different exocytosis stages has not been defined. Here, we demonstrated that PTP-MEG2 44 controls multiple steps of catecholamine secretion. Biochemical and crystallographic 45 analysis revealed key residues that govern the PTP-MEG2 and NSF-pY 83 site interactions, 46 specify PTP-MEG2 substrate selectivity and modulate the fusion of catecholamine-47 containing vesicles. Unexpectedly, delineation of the PTP-MEG2 mutants along with the 48 NSF interface revealed that PTP-MEG2 controls the fusion pore opening through another 49 unknown substrate. Utilizing a bioinformatics search and biochemical and 50 electrochemical screening, we uncovered that PTP-MEG2 regulates the opening and 51 extension of the fusion pore by dephosphorylating the MUNC18-1 Y 145 site, which is 52 associated with epileptic encephalopathy. The crystal structure of the PTP-53 MEG2/phospho-MUNC18-1-pY 145 segment confirmed the interaction of PTP-MEG2 with 54MUNC18-1 through a distinct structural basis. Our studies extended mechanism insights 55 in complex exocytosis processes. 56 57 KEY WORDS: 58 59 exocytosis, tyrosine phosphorylation, structure, catecholamine, PTP-MEG2 60 61 HIGHLIGHTS: 62 63 PTP-MEG2 regulates multiple steps of exocytosis. 64 A crystal structure of the PTP-MEG2/phosphor-NSF-pY 83 segment was obtained. 65 Functional delineation of the PTP-MEG2/NSF interface resulted in uncovering unknown 66 PTP-MEG2 substrates. 67 PTP-MEG2 regulates fusion pore opening and extension through the MUNC18-1 pY 145 68 site. 69 The distinct structural bases of the recognition of substrates by PTP-MEG2 allows 70 selective inhibitor design. 71 72 73 74 75physiological processes (Wu et al., 2014, Dittman and Ryan, 2019, Neher and Brose, 2018. 79The contents of secreted vesicles include neuronal transmitters, immune factors and other 80 hormones (Alvarez de Toledo et al., 1993, Sudhof, 2013, Magadmi et al., 2019. There are three 81 main exocytosis pathways in secretory cells, namely, full-collapse fusion, kiss-and-run, and 82 compound exocytosis, which possess different secretion rates and lease amount (Sudhof, 2004). 83It was previously reported that the phosphorylation of critical proteins at serine/threonine or 84 tyrosine residues participated in stimulus-secretion coupling in certain important exocytosis 85 processes, for example, the secretion of insulin from pancreatic β cells and of catecholamine 86 from the adrenal medulla (Ortsater et al., 2014, Seino et al., 2009, Laidlaw et al., 2017. 87However, the exact roles of protein tyrosine phosphatases (PTPs) in the regulation of key 88 hormone secretion procedures are not fully understood. 89The 68-kDa PTP-MEG2, encoded by ptpn9, is a non-receptor classical PTP encompassing a 90 unique N-terminal domain with homology to the human CRAL/TRIO domain and yeast Sec14p 91 (Alonso et al., 2004, Gu et al., 1992, Zhang et al., 2012, Zhang e...

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“…A recent study highlighted the central role played by a complex of soluble-N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) in metabolic diseases, [8,9] which are also involved in the pathogenesis of type 2 diabetes mellitus (T2DM) [10] as well as in cardiac functions. [11–13] The SNARE-complex includes the two t-SNARE proteins, synaptosomal protein of 25 kDa (SNAP25) and syntaxin 1A (Stx-1A), as well as the v-SNARE protein VAMP2.…”

Section: Introductionmentioning

confidence: 99%

The Syntaxin-1A gene single nucleotide polymorphism rs4717806 associates with the risk of ischemic heart disease

et al. 2019

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Ischemic heart disease (IHD) has a genetic predisposition and a number of cardiovascular risk factors are known to be affected by genetic factors. Development of metabolic syndrome and insulin resistance, strongly influenced by lifestyle and environmental factors, frequently occur in subjects with a genetic susceptibility. The definition of genetic factors influencing disease susceptibility would allow to identify individuals at higher risk and thus needing to be closely monitored. To this end, we focused on a complex of soluble-N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), playing an important role in metabolic syndrome and insulin resistance, involved in endothelial dysfunction and heart disease. We assessed if genetic variants of the SNARE genes are associated with IHD. SNAP25 rs363050 , Stx-1A rs4717806 , rs2293489 , and VAMP2 26bp ins/del genetic polymorphisms were analyzed in a cohort of 100 participants who underwent heart surgery; 56 of them were affected by IHD, while 44 were not. A statistical association of plasma glycemia and insulin resistance, calculated as Triglyceride glucose (TyG) index, was observed in IHD ( P < .001 and P = .03, respectively) after binomial logistic stepwise regression analysis, adjusted by age, gender, diabetes positivity, waist circumference, and cholesterol plasma level. Among genetic polymorphisms, rs4717806(A) and rs2293489(T) , as well as the rs4717806 – rs2293489 (A-T) haplotype were associated with higher risk for IHD ( Pc = .02; Pc = .02; P = .04, respectively). Finally, a statistical association of rs4717806(AA) genotype with higher TyG index in IHD patients ( P = .03) was highlighted by multiple regression analysis considering log-transformed biochemical parameters as dependent variable and presence of coronary artery disease, age, gender, waist circumference, presence of diabetes as predictors. These results point to a role of the Stx-1A rs4717806 SNP in IHD, possibly due to its influence on Stx-1A expression and, as a consequence, on insulin secretion and glucose metabolism.

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SNARE phosphorylation: a control mechanism for insulin-stimulated glucose transport and other regulated exocytic events

Cited by 16 publications

References 48 publications

Unraveling the mechanisms of calcium-dependent secretion

Unraveling the mechanisms of calcium-dependent secretion

PTP-MEG2 regulates quantal size and fusion pore opening through two distinct structural bases and substrates

The Syntaxin-1A gene single nucleotide polymorphism rs4717806 associates with the risk of ischemic heart disease

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