Matthew Seaman

Publications (27) View all

• Article: The hereditary spastic paraplegia protein strumpellin: Characterisation in neurons and of the effect of disease mutations on WASH complex assembly and function.

  Caroline Freeman, Matthew N J Seaman, Evan Reid
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  ABSTRACT: Mutations in the gene encoding strumpellin cause autosomal dominant hereditary spastic paraplegia (HSP), in which there is degeneration of corticospinal tract axons. Strumpellin is a component of the WASH complex, an actin-regulating complex that is recruited to endosomes by interactions with the retromer complex. The WASH complex and its relationship to retromer have not been fully characterised in neurons, and the molecular pathological mechanism of strumpellin mutation is unclear. Here we demonstrate that the WASH complex assembles in brain, where it interacts with retromer. Members of both complexes co-localise with each other and with endosomes in primary cortical neurons, and are present in somato-dendritic and axonal compartments. We show that strumpellin is not required for normal transferrin receptor traffic, but is required for the correct subcellular distribution of the β-2-adrenergic receptor. However, strumpellin disease mutations do not affect its incorporation into the WASH complex or its subcellular localisation, nor do they have a dominant effect on functions of the WASH complex, including regulation of endosomal tubulation, transferrin receptor traffic or β-2-adrenergic receptor localisation. Models of the WASH complex indicate that it contains a single strumpellin molecule, so in patients with strumpellin mutations, complexes containing wild-type and mutant strumpellin should be present in equal numbers. In most cell types this would provide sufficient functional WASH to allow normal cellular physiology. However, owing to the demands on membrane traffic imposed by their exceptionally long axons, we suggest that corticospinal neurons are especially vulnerable to reductions in functional WASH.
  Biochimica et Biophysica Acta 10/2012; · 4.66 Impact Factor
• Article: Correction: The Fifth Adaptor Protein Complex.

  Jennifer Hirst, Lael D Barlow, Gabriel Casey Francisco, Daniela A Sahlender, Matthew N J Seaman, Joel B Dacks, Margaret S Robinson
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  ABSTRACT: [This corrects the article on p. e1001170 in vol. 9.].
  PLoS Biology 03/2012; 10(3). · 11.45 Impact Factor
• Article: Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing.

  Anja W Fjorback, Matthew Seaman, Camilla Gustafsen, Arnela Mehmedbasic, Suzanne Gokool, Chengbiao Wu, Daniel Militz, Vanessa Schmidt, Peder Madsen, Jens R Nyengaard, Thomas E Willnow, Erik Ilsø Christensen, William B Mobley, Anders Nykjær, Olav M Andersen
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  ABSTRACT: sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD.
  Journal of Neuroscience 01/2012; 32(4):1467-80. · 7.11 Impact Factor
• Article: Recruitment of the endosomal WASH complex is mediated by the extended 'tail' of Fam21 binding to the retromer protein Vps35.

  Michael E Harbour, Sophia Y Breusegem, Matthew N J Seaman
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  ABSTRACT: The retromer complex is a conserved endosomal protein sorting complex that sorts membrane proteins into nascent endosomal tubules. The recognition of membrane proteins is mediated by the cargo-selective retromer complex, a stable trimer of the Vps35 (vacuolar protein sorting 35), Vps29 and Vps26 proteins. We have recently reported that the cargo-selective retromer complex associates with the WASH (Wiskott-Aldrich syndrome homologue) complex, a multimeric protein complex that regulates tubule dynamics at endosomes. In the present study, we show that the retromer-WASH complex interaction occurs through the long unstructured 'tail' domain of the WASH complex-Fam21 protein binding to Vps35, an interaction that is necessary and sufficient to target the WASH complex to endosomes. The Fam21-tail also binds to FKBP15 (FK506-binding protein 15), a protein associated with ulcerative colitis, to mediate the membrane association of FKBP15. Elevated Fam21-tail expression inhibits the association of the WASH complex with retromer, resulting in increased cytoplasmic WASH complex. Additionally, overexpression of the Fam21-tail results in cell-spreading defects, implicating the activity of the WASH complex in regulating the mobilization of membrane into the endosome-to-cell surface pathway.
  Biochemical Journal 11/2011; 442(1):209-20. · 4.90 Impact Factor
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  Available from: Matthew Seaman

  Article: The fifth adaptor protein complex.

  Jennifer Hirst, Lael D Barlow, Gabriel Casey Francisco, Daniela A Sahlender, Matthew N J Seaman, Joel B Dacks, Margaret S Robinson
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  ABSTRACT: Adaptor protein (AP) complexes sort cargo into vesicles for transport from one membrane compartment of the cell to another. Four distinct AP complexes have been identified, which are present in most eukaryotes. We report the existence of a fifth AP complex, AP-5. Tagged AP-5 localises to a late endosomal compartment in HeLa cells. AP-5 does not associate with clathrin and is insensitive to brefeldin A. Knocking down AP-5 subunits interferes with the trafficking of the cation-independent mannose 6-phosphate receptor and causes the cell to form swollen endosomal structures with emanating tubules. AP-5 subunits can be found in all five eukaryotic supergroups, but they have been co-ordinately lost in many organisms. Concatenated phylogenetic analysis provides robust resolution, for the first time, into the evolutionary order of emergence of the adaptor subunit families, showing AP-3 as the basal complex, followed by AP-5, AP-4, and AP-1 and AP-2. Thus, AP-5 is an evolutionarily ancient complex, which is involved in endosomal sorting, and which has links with hereditary spastic paraplegia.
  PLoS Biology 10/2011; 9(10):e1001170. · 11.45 Impact Factor