{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,9,21]],"date-time":"2024-09-21T11:56:32Z","timestamp":1726919792242},"reference-count":43,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2017,6,14]],"date-time":"2017-06-14T00:00:00Z","timestamp":1497398400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100007108","name":"George Washington University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2017,7]]},"abstract":"<jats:p>Mutations of human <jats:styled-content style=\"fixed-case\">MID<\/jats:styled-content>1 are associated with X\u2010linked Opitz G Syndrome (<jats:styled-content style=\"fixed-case\">XLOS<\/jats:styled-content>), which is characterized by midline birth defects. <jats:styled-content style=\"fixed-case\">XLOS<\/jats:styled-content>\u2010observed mutations within the <jats:styled-content style=\"fixed-case\">MID<\/jats:styled-content>1 B\u2010box1 domain are associated with cleft lip\/palate, wide\u2010spaced eyes and hyperspadias. Three of the four <jats:styled-content style=\"fixed-case\">XLOS<\/jats:styled-content>\u2010observed mutations in the B\u2010box1 domain results in unfolding but the structural and functional effects of the P151L mutation is not characterized. Here, we demonstrate that the P151L mutation does not disrupt the overall tertiary structure of the B\u2010box1 domain and the adjacent domains. In fact, <jats:styled-content style=\"fixed-case\">MID<\/jats:styled-content>1 E3 ligase activity is slightly enhanced. However, the P151L mutation disrupted the ability of <jats:styled-content style=\"fixed-case\">MID<\/jats:styled-content>1 to catalyze the poly\u2010ubiquitination of alpha4, a novel regulator of <jats:styled-content style=\"fixed-case\">PP<\/jats:styled-content>2A. This observation is consistent with results observed with the other three structure\u2010destabilizing B\u2010box1 mutations in targeting alpha4 but not <jats:styled-content style=\"fixed-case\">PP<\/jats:styled-content>2A. Alpha4 is shown to bind and sequester the catalytic subunit of <jats:styled-content style=\"fixed-case\">PP<\/jats:styled-content>2A and protect it from <jats:styled-content style=\"fixed-case\">MID<\/jats:styled-content>1\u2010mediated ubiquitination and as a result, an increase in alpha4 can contribute to an increase in <jats:styled-content style=\"fixed-case\">PP<\/jats:styled-content>2A, playing a greater role in midline development during embryogenesis.<\/jats:p>","DOI":"10.1111\/febs.14121","type":"journal-article","created":{"date-parts":[[2017,5,26]],"date-time":"2017-05-26T11:36:55Z","timestamp":1495798615000},"page":"2183-2193","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Structural and functional observations of the P151L <scp>MID<\/scp>1 mutation reveal alpha4 plays a significant role in X\u2010linked Opitz Syndrome"],"prefix":"10.1111","volume":"284","author":[{"given":"Katharine 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