5im8 | pdb_00005im8
Solution Structure of the Microtubule-Targeting COS Domain of MID1
Structural highlights
DiseaseTRI18_HUMAN Defects in MID1 are the cause of Opitz GBBB syndrome 1 (OGS1) [MIM:300000. A congenital midline malformation syndrome characterized by hypertelorism, genital-urinary defects such as hypospadias in males and splayed labia in females, lip-palate-laryngotracheal clefts, imperforate anus, developmental delay and congenital heart defects. Note=MID1 mutations produce proteins with a decreased affinity for microtubules.[1] [2] [3] [4] FunctionTRI18_HUMAN Has E3 ubiquitin ligase activity towards IGBP1, promoting its monoubiquitination, which results in deprotection of the catalytic subunit of protein phosphatase PP2A, and its subsequent degradation by polyubiquitination.[5] [6] [7] Publication Abstract from PubMedThe human MID1 protein is required for the proper development during embryogenesis. Mutations of MID1 are associated with X-linked Opitz G syndrome, characterized by midline anomalies. MID1 associates with the microtubules and functions as an ubiquitin E3 ligase, targeting protein phosphatase 2A for ubiquitin-mediated regulation. The mechanism of microtubule association is not known. Recently, a 60-amino acid region termed the COS box/domain was identified at the C-terminal end of the coiled-coil (CC) domain that facilitates microtubule localization. Insertion of the MID1 COS domain at the C-terminal end of the CC domain of a non-microtubule associated TRIM protein confers microtubule localization. Here, we report the solution structure of the COS domain of MID1. The domain adopts a helix-loop-helix structure in which the N- and C-terminal ends are in close proximity. Hydrophobic residues stabilizing the interaction of the two alpha-helices form a central hydrophobic core. The loop separating the alpha-helices is structured, with two of its hydrophobic residues making contact with the central core. On the outer surface, positively charged residues form a distinct basic patch near the termini that we postulate is important for microtubule binding. A model of the structure of the preceding coiled-coil and COS domains (CC-COS) show that the COS domain forms a helical bundle at the C-terminal end of the CC domain similar to the spectrin-like fold observed with some known microtubule-binding proteins. Interestingly, the CC-COS domains bind to microtubules, demonstrating for the first time that MID1 can directly associate with the microtubules. This article is protected by copyright. All rights reserved. Solution Structure of the Microtubule-Targeting COS Domain of MID1.,Wright KM, Du H, Dagnachew M, Massiah MA FEBS J. 2016 Jul 1. doi: 10.1111/febs.13795. PMID:27367845[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||
