{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T15:27:12Z","timestamp":1788017232393,"version":"build-2784847793"},"reference-count":34,"publisher":"Life Science Alliance, LLC","issue":"5","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["life-science-alliance.org"],"crossmark-restriction":true},"short-container-title":["Life Sci. Alliance"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:p>Single-nucleotide polymorphisms (SNPs) in <jats:italic>RNF213<\/jats:italic>, which encodes a 591-kD protein with AAA+ ATPase and RING E3 domains, are associated with a rare, autosomal dominant cerebrovascular disorder, moyamoya disease (MMD). MMD-associated SNPs primarily localize to the C-terminal region of <jats:italic>RNF213<\/jats:italic>, and some affect conserved residues in the RING domain. Although the autosomal dominant inheritance of MMD could most easily explained by RNF213 gain-of-function, the type of ubiquitylation catalyzed by RNF213 and the effects of MMD-associated SNPs on its E3 ligase activity have remained unclear. We found that RNF213 uses the E2-conjugating enzymes UBE2D2 and UBE2L3 to catalyze distinct ubiquitylation events. RNF213-UBED2 catalyzes K6 and, to a lesser extent, K48-dependent poly-ubiquitylation in vitro, whereas RNF213-UBE2L3 catalyzes K6-, K11-, and K48-dependent poly-ubiquitylation events. MMD-associated SNPs encode proteins with decreased E3 activity, and the most frequent MMD allele, <jats:italic>RNF213<\/jats:italic><jats:sup><jats:italic>R4810K<\/jats:italic><\/jats:sup>, is a dominant-negative mutant that decreases ubiquitylation globally. By contrast, MMD-associated <jats:italic>RNF213<\/jats:italic> SNPs do not affect ATPase activity. Our results suggest that decreased RNF213 E3 ligase activity is central to MMD pathogenesis.<\/jats:p>","DOI":"10.26508\/lsa.202000807","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T19:45:16Z","timestamp":1644349516000},"page":"e202000807","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["MMD-associated <i>RNF213<\/i> SNPs encode dominant-negative alleles that globally impair ubiquitylation"],"prefix":"10.26508","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-7497","authenticated-orcid":true,"given":"Abhishek","family":"Bhardwaj","sequence":"first","affiliation":[{"name":"Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York University, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S","family":"Banh","sequence":"additional","affiliation":[{"name":"Laura and Isaac 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