3v31
From Proteopedia
Crystal Structure of the Peptide Bound Complex of the Ankyrin Repeat Domains of Human ANKRA2
Structural highlights
Disease[HDAC4_HUMAN] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:600430]. A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism.[1] Function[ANRA2_HUMAN] May facilitate endocytosis by linking megalin to components of the cytoskeleton or endocytic machinery. [HDAC4_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D.[2] Publication Abstract from PubMedAnkyrin repeat family A protein 2 (ANKRA2) interacts with the plasma membrane receptor megalin and the class IIa histone deacetylases HDAC4 and HDAC5. We report that the ankyrin repeat domains of ANKRA2 and its close paralog regulatory factor X-associated ankyrin-containing protein (RFXANK) recognize a PxLPxI/L motif found in diverse binding proteins, including HDAC4, HDAC5, HDAC9, megalin, and regulatory factor X, 5 (RFX5). Crystal structures of the ankyrin repeat domain of ANKRA2 in complex with its binding peptides revealed that each of the middle three ankyrin repeats of ANKRA2 recognizes a residue from the PxLPxI/L motif in a tumbler-lock binding mode, with ANKRA2 acting as the lock and the linear binding motif serving as the key. Structural analysis showed that three disease-causing mutations in RFXANK affect residues that are critical for binding to RFX5. These results suggest a fundamental principle of longitudinal recognition of linear sequences by a repeat-type domain. In addition, phosphorylation of serine 350, a residue embedded within the PxLPxI/L motif of HDAC4, impaired the binding of ANKRA2 but generated a high-affinity docking site for 14-3-3 proteins, which may help sequester this HDAC in the cytoplasm. Thus, the binding preference of the PxLPxI/L motif is signal-dependent. Furthermore, proteome-wide screening suggested that a similar phosphorylation-dependent switch may operate in other pathways. Together, our findings uncover a previously uncharacterized sequence- and signal-dependent peptide recognition mode for a repeat-type protein domain. Sequence-Specific Recognition of a PxLPxI/L Motif by an Ankyrin Repeat Tumbler Lock.,Xu C, Jin J, Bian C, Lam R, Tian R, Weist R, You L, Nie J, Bochkarev A, Tempel W, Tan CS, Wasney GA, Vedadi M, Gish GD, Arrowsmith CH, Pawson T, Yang XJ, Min J Sci Signal. 2012 May 29;5(226):ra39. PMID:22649097[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Histone deacetylase | Human | Large Structures | Arrowsmith, C H | Bian, C B | Bochkarev, A | Bountra, C | Edwards, A M | Kania, J | Lam, R | Min, J | Structural genomic | Weigelt, J | Xu, C | Ank repeat | Ankra2 | Hdac4 | Protein binding | Sgc
