2006
DOI: 10.1016/j.str.2006.01.012
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The Endosome-Associated Protein Hrs Is Hexameric and Controls Cargo Sorting as a “Master Molecule”

Abstract: The structure of the endosomal-associated protein, Hrs, has been determined with cryo-electron microscopy. Hrs interacts with a number of proteins, including SNAP-25 and STAM1, forming a complex that binds ubiquitin moieties. Analytical ultracentrifugation studies revealed that Hrs exists as a hexamer. The symmetry and the structure of the hexameric form of Hrs were determined with the single-particle reconstruction method. Hrs comprises three antiparallel dimers with a central core and distinct caps on either… Show more

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Cited by 27 publications
(29 citation statements)
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References 37 publications
(65 reference statements)
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“…Another study has recently suggested that recombinant Hrs purified in the absence of STAM may form hexamers, again supporting the idea that Hrs can self-associate (37). We failed to observe the formation of Hrs hexamers in extracts from stam⌬ animals.…”
Section: Discussionsupporting
confidence: 87%
See 1 more Smart Citation
“…Another study has recently suggested that recombinant Hrs purified in the absence of STAM may form hexamers, again supporting the idea that Hrs can self-associate (37). We failed to observe the formation of Hrs hexamers in extracts from stam⌬ animals.…”
Section: Discussionsupporting
confidence: 87%
“…The DUIM of human Hrs has been shown to bind ubiquitin with affinities ranging from 190 -450 M (11,27), and studies of the STAM UIM have been similarly inconsistent (13,27). In one case, analysis of the Hrs VHS domain revealed extremely weak binding to ubiquitin (K d ϭ 1.4 mM), while another study demonstrated that binding to ubiquitin was not detectable to an identical region (12,37). Such variation may be a consequence of the methodology used.…”
Section: Discussionmentioning
confidence: 99%
“…4). In the absence of STAM proteins, purified mouse Hrs forms a hexameric homooligomer, which is able to bind to endosomal membranes in vitro (12). In contrast, we found for the first time that STAMunbound Hrs exists predominantly as a monomer in vivo (Fig.…”
Section: Discussionmentioning
confidence: 67%
“…Thus, multiple UBDs in the Hrs⅐STAM complex seem to strengthen the overall affinity for ubiquitylated cargo and enable effective cargo sorting. Interestingly, in the absence of STAM, purified Hrs forms a cylindrical hexameric complex composed of three sets of antiparallel pairs (12). The multiple UBDs in the Hrs hexamer may also facilitate the binding to ubiquitylated cargo.…”
mentioning
confidence: 99%
“…ESCRT-0 partitions the endocytosed material arriving on the early endosomes between recycling and the multivesicular body (9 -11) and interacts with downstream ESCRT machinery (12, 13) responsible for commitment of selected cargo for degradation (14). Due to its ability to influence both recycling and degradation (15), Hrs has been termed a "master regulator" of endocytosis. Although the mechanisms by which Hrs globally regulates endosomal sorting remain ambiguous, there is a clear phenotypic role for reversible ubiquitination as a signal directing ESCRT-0-mediated endocytosis.…”
mentioning
confidence: 99%