Structural Identification of the Vps18 β-Propeller Reveals a Critical Role in the HOPS Complex Stability and Function

Behrmann, Heide; Lürick, Anna; Kuhlee, Anne; Balderhaar, Henning Kleine; Bröcker, Cornelia; Kümmel, Daniel; Engelbrecht-Vandré, Siegfried; Gohlke, U.; Raunser, Stefan; Heinemann, Udo; Ungermann, Christian

doi:10.1074/jbc.m114.602714

Cited by 14 publications

(14 citation statements)

References 42 publications

(30 reference statements)

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“…The class C tether subunits are predicted to contain an N‐terminal β‐propeller and an C‐terminal α‐helical solenoid, a domain architecture commonly found in trafficking proteins . This was confirmed by crystal structures of the Vps18 propeller and a fragment of the Vps16 solenoid in complex with Vps33 (Figure A,B) . Vps33 is the exception among class C subunits, representing an S/M family protein and showing the characteristic arch‐shaped structure .…”

Section: Class C Vps Tethersmentioning

confidence: 61%

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Structure of membrane tethers and their role in fusion

Ungermann

Kümmel

2019

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Vesicular transport between different membrane compartments is a key process in cell biology required for the exchange of material and information. The complex machinery that executes the formation and delivery of transport vesicles has been intensively studied and yielded a comprehensive view of the molecular principles that underlie the budding and fusion process. Tethering also represents an essential step in each trafficking pathway. It is mediated by Rab GTPases in concert with so-called tethering factors, which constitute a structurally diverse family of proteins that share a similar role in promoting vesicular transport. By simultaneously binding to proteins and/or lipids on incoming vesicles and the target compartment, tethers are thought to bridge donor and acceptor membrane. They thus provide specificity while also promoting fusion. However, how tethering works at a mechanistic level is still elusive.We here discuss the recent advances in the structural and biochemical characterization of tethering complexes that provide novel insight on how these factors might contribute the efficiency of fusion. K E Y W O R D S CATCHR, golgin, membrane fusion, Rab GTPases, Sec1/Munc18, SNARE, tethering, vesicular transport 1 | INTRODUCTION Compartmentalization of eukaryotic cells into organelles is the prerequisite for the formation of chemically distinct environments that allow the implementation of specialized functions. Communication and the exchange of substances between different membrane compartments, however, is also essential for proper function of cells. In the endomembrane system, comprising the secretory pathway and the endolysosomal system, membrane vesicles have long been established as transport carriers that fulfill this function. 1 Trafficking can be dissected into distinct steps: at the donor membrane, small GTPases like Arf, Sar1 or Arf-like (Arl) and coat proteins, which assemble into vesicle coat complexes, orchestrate cargo sorting and concentration followed by vesicle budding and scission. Vesicles are then transported along cytoskeletal filaments with the help of motor proteins. At the target membrane, incoming vesicles are recruited by Rab GTPases and tethering factors. Rabs are markers of organelle identity and conserved part of the fusion machinery. 2,3 Common to all small GTPases, Rabs cycle between an inactive GDP-bound and an active GTP-bound form, and only the latter form can interact with effectors that mediate downstream functions of Rabs. Tethering factors from different classes are evolutionarily unrelated proteins and structurally divers, but share a function as Rab effectors and are thought to bridge two opposing membranes. After tethering, SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptor) on each membrane are necessary. 4 SNARE proteins drive fusion, but function of SNAREs requires S/M (Sec1/Munc18) family proteins that act as chaperones of SNARE assembly and the NSF (N-ethylmaleimide sensitive factor) ATPase that with the adaptor protein α-SNAP disasse...

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Section: Class C Vps Tethersmentioning

confidence: 61%

“…A, Structure of the subcomplex of the S/M protein Vps33 (teal) and the part of the C‐terminal α solenoid of Vps16 (PDBID 4KMO). B, Structure of the N‐terminal β propeller of Vps18 (PDBID: 4UUY). C, 3D reconstruction of compact HOPS by negative stain EM (EMD‐2280).…”

Section: Class C Vps Tethersmentioning

confidence: 99%

Structure of membrane tethers and their role in fusion

Ungermann

Kümmel

2019

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“…It is part of HOPS and CORVET, two hexameric tethering complexes, which localise to lysosomes and endosomes, respectively. Human VPS11 is a 921 amino acids protein, which consists of three conserved domains: a predicted WD40 domain (AA 142-292) is likely a part of the N-terminal β-propeller as identified for the Vps18 protein,18 two clathrin domains (AA 417-536, 598-727), which presumably add up as part of a C-terminal alfa-solenoid,19 a RING-finger domain (AA 821-860) and a C-terminal domain (AA 862-909). RING-finger domains are made of six spaced cysteines [C-X(2)-C-X(9,39)-C-X(1,3)-H-X(2,3)-[NCH]-X(2)- C -X(4,48)-C-X(2)-C] and typically bind two zinc atoms.…”

Section: Discussionmentioning

confidence: 99%

Hypomyelination and developmental delay associated withVPS11mutation in Ashkenazi-Jewish patients

et al. 2015

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“…HOPS and CORVET subunits are required for early embryonic development and their knock-out is usually lethal in mice [20,21]. CORVET/HOPS subunits have a similar structure: a β-propeller domain at the N terminus with zinc-finger domain at the C-terminal [22,23]. Electron microscopy analyses revealed that HOPS and CORVET shares a similar architecture and forms an elongated particle with two Rab-binding sites formed by Vps39/Vps41 (HOPS) and Vps3/VPS8 (CORVET) at opposite ends [24,25].…”

Section: Hops and Corvetmentioning

confidence: 99%

Mucopolysaccharidosis-Plus Syndrome

Vasilev

Syromyatnikova

Otomo

2020

IJMS

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Previously, we reported a novel disease of impaired glycosaminoglycans (GAGs) metabolism without deficiency of known lysosomal enzymes—mucopolysaccharidosis-plus syndrome (MPSPS). MPSPS, whose pathophysiology is not elucidated, is an autosomal recessive multisystem disorder caused by a specific mutation p.R498W in the VPS33A gene. VPS33A functions in endocytic and autophagic pathways, but p.R498W mutation did not affect both of these pathways in the patient’s skin fibroblast. Nineteen patients with MPSPS have been identified: seventeen patients were found among the Yakut population (Russia) and two patients from Turkey. Clinical features of MPSPS patients are similar to conventional mucopolysaccharidoses (MPS). In addition to typical symptoms for conventional MPS, MPSPS patients developed other features such as congenital heart defects, renal and hematopoietic disorders. Diagnosis generally requires evidence of clinical picture similar to MPS and molecular genetic testing. Disease is very severe, prognosis is unfavorable and most of patients died at age of 10–20 months. Currently there is no specific therapy for this disease and clinical management is limited to supportive and symptomatic treatment.

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Structural Identification of the Vps18 β-Propeller Reveals a Critical Role in the HOPS Complex Stability and Function

Cited by 14 publications

References 42 publications

Structure of membrane tethers and their role in fusion

Structure of membrane tethers and their role in fusion

Hypomyelination and developmental delay associated withVPS11mutation in Ashkenazi-Jewish patients

Mucopolysaccharidosis-Plus Syndrome

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