Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex

Lees, Joshua A.; Li, Peiqi; Kumar, Nikit; Weisman, Lois S.; Reinisch, Karin M

doi:10.1016/j.molcel.2020.10.003

Cited by 59 publications

(76 citation statements)

References 29 publications

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“…The first study to assess NBEAL2 binding utilized the PH‐BEACH, WD40 domains with a C‐terminal tag expressed in HEK293 cells combined with affinity purification and mass spectrometry 17 . After validation using immunoprecipitation and ligation proximity experiments, three proteins were identified: DOCK7, a guanine nucleotide exchange factor (GEF) for RAC1/CDC42; SEC16A, which interacts directly with several components of the COPII machinery at the endoplasmic reticulum‐Golgi intermediate compartment (ERGIC) to facilitate the delivery of cargo; 35 and VAC14, which forms a ternary complex composed of five copies of VAC14 and one copy each of the lipid kinase PIKfyve and the lipid phosphatase FIG4 that regulates the level of phosphatidylinositol 3,5‐bisphosphate (PtdIns[3,5]P2) 36 . DOCK7 is decreased in platelets from GPS patients and NBEAL2‐null mice, 17 and a truncation within the DHR‐1 domain of DOCK7 causes bleeding in mice 37,38 .…”

Section: Nbeal2 Function In Megakaryocytes and Plateletsmentioning

confidence: 99%

Gray platelet syndrome: NBEAL2 mutations are associated with pathology beyond megakaryocyte and platelet function defects

Pluthero

Kahr

2021

Journal of Thrombosis and Haemostasis

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Section: Nbeal2 Function In Megakaryocytes and Plateletsmentioning

confidence: 99%

Gray platelet syndrome: NBEAL2 mutations are associated with pathology beyond megakaryocyte and platelet function defects

Pluthero

Kahr

2021

Journal of Thrombosis and Haemostasis

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“…These opposing lipid-modifying enzymes are members of a single complex, scaffolded by Vac14. [67][68][69] The tripartite complex is conserved widely in eukaryotes, including humans, where the kinase is called PIKfyve and the other two proteins retain their yeast names. The mechanism of action of Vac7 does not involve altering the assembly or membrane targeting of the Fab1 (PIKfyve) complex with Vac14 and Fig4.…”

Section: Discussionmentioning

confidence: 99%

“…67,70 Nevertheless, the cytoplasmic domain of Vac7 strongly interacts with Vac14. 72 The interaction interface requires almost the whole of Vac14, which has different binding sites along its length, 69 which suggests that Vac7 may bind not to Vac14 alone, but also to partners of Vac14.…”

Section: Discussionmentioning

confidence: 99%

TMEM106B in humans and Vac7 and Tag1 in yeast are predicted to be lipid transfer proteins

Levine¹

2021

Preprint

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TMEM106B is an integral membrane protein of late endosomes and lysosomes involved in neuronal function, its over-expression being associated with familial frontotemporal lobar degeneration, and under-expression linked to hypomyelination. It has also been identified in multiple screens for host proteins required for productive SARS-CoV2 infection. Because standard approaches to understand TMEM106B at the sequence level find no homology to other proteins, it has remained a protein of unknown function. Here, the standard tool PSI-BLAST was used in a non-standard way to show that the lumenal portion of TMEM106B is a member of the LEA 2 domain superfamily. The non-standard tools (HMMER, HHpred and trRosetta) extended this to predict two yeast LEA 2 proteins in the lumenal domains of the degradative vacuole, equivalent to the lysosome: one in Vac7, a regulator of PI(3,5)P2 production, and three in Tag1 which signals to terminate autophagy. Further analysis of previously unreported LEA 2 structures indicated that LEA 2 domains have a long, conserved lipid binding groove. This implies that TMEM106B, Vac7 and Tag1 may all be lipid transfer proteins in the lumen of late endocytic organelles.

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“…In addition, it plays a role in several trafficking events associated with the endocytic pathway. In PIKfyve active site resides in Zinc finger domain [30,31]. Twelve peptides showed maximum interactions and among them, IQKVAGTW showed the most intimacy with a docking score of − 10.13 (Fig.…”

Section: Phosphatidylinositol 3 Phosphate 5 Kinase (Pikfyve)mentioning

confidence: 99%

Milk Peptides as Novel Multi‐Targeted Therapeutic Candidates for SARS-CoV2

2021

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The COVID-19, an acute respiratory syndrome caused by SARS-CoV2 is a major catastrophic event of the twenty first century. Relentless efforts for the development of effective pharmaco-therapeutics are in progress but the respite is the development of effective vaccines. However, monotherapy might not always exhibit complete efficacy and may culminate in the rapid evolution of drug-resistant viral strains. Hence, simultaneous modulation of multiple druggable targets not only enhances therapeutic efficacy but also quell the prospects of mutant viruses. Currently, milk peptides have bloomed beyond just being a quintessential part of nutrition to prominent therapeutic implications in human health and diseases. Hence, we have focused on colostrum/milk peptides as they have already been acknowledged for their high potency, target specificity with significantly low or no side effects and bio-toleration. The results presented provide a conceptual strategy for the rational designing of prospective multitargeted peptide inhibitors for SARS-CoV2. Supplementary Information The online version contains supplementary material available at 10.1007/s10930-021-09983-8.

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Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-Biochemical Analysis of the PIKfyve Lipid Kinase Complex

Cited by 59 publications

References 29 publications

Gray platelet syndrome: NBEAL2 mutations are associated with pathology beyond megakaryocyte and platelet function defects

Gray platelet syndrome: NBEAL2 mutations are associated with pathology beyond megakaryocyte and platelet function defects

TMEM106B in humans and Vac7 and Tag1 in yeast are predicted to be lipid transfer proteins

Milk Peptides as Novel Multi‐Targeted Therapeutic Candidates for SARS-CoV2

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