Structural and functional observations of the P151L MID1 mutation reveal alpha4 plays a significant role in X-linked Opitz Syndrome.
Mutations of human MID1 are associated with X-linked Opitz G Syndrome (XLOS), which is characterized by midline birth defects. XLOS-observed mutations within the MID1 B-box1 domain are associated with cleft lip/palate, wide-spaced eyes and hyperspadias. Three of the four XLOS-observed mutations in the B-box1 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-box1 domain and the adjacent domains. In fact, MID1 E3 ligase activity is slightly enhanced. However, the P151L mutation disrupted the ability of MID1 to catalyze the poly-ubiquitination of alpha4, a novel regulator of PP2A. This observation is consistent with results observed with the other three structure-destabilizing B-box1 mutations in targeting alpha4 but not PP2A. Alpha4 is shown to bind and sequester the catalytic subunit of PP2A and protect it from MID1-mediated ubiquitination and as a result, an increase in alpha4 can contribute to an increase in PP2A, playing a greater role in midline development during embryogenesis.
['Wright|Katharine M|KM|', 'Du|Haijuan|H|', 'Massiah|Michael A|MA|']
D000595:Amino Acid Sequence D002972:Cleft Palate D004947:Esophagus D040181:Genetic Diseases, X-Linked D006801:Humans D006972:Hypertelorism D007021:Hypospadias D008868:Microtubule Proteins D008958:Models, Molecular D009154:Mutation D009687:Nuclear Proteins D000072417:Protein Domains D054648:Protein Phosphatase 2 D011499:Protein Processing, Post-Translational D017434:Protein Structure, Tertiary D017386:Sequence Homology, Amino Acid D013379:Substrate Specificity D014157:Transcription Factors D044767:Ubiquitin-Protein Ligases D054875:Ubiquitination
E3 ligase PP2A Ubiquitination B-box TRIM