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      Mutually exclusive binding of APPL(PH) to BAR domain and Reptin regulates β-catenin dependent transcriptional events.

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          Abstract

          Reptin functions in a wide range of biological processes including chromatin remodelling, nucleolar organization and transcriptional regulation of WNT signalling. As β-catenin dependent transcriptional repression and activation events involve binding of Reptin and histone deacetylase 1 to APPL endocytic proteins, this complex has become an important target to identify molecules governing endocytic processes and WNT signalling. Here, we describe the structural basis of APPL binding to Reptin to explore their mode of binding in context with APPL1/APPL2 dimerization. There is an evidence that both PH and BAR domains of APPL proteins exhibit alternately conserved regions involved in hetero-dimerization process and our in-silico data also corroborate this fact. Moreover, APPL2(PH) domain binds to the BAR domain region encompassing a nuclear localization signal. We conclude that APPL(PH) binding to BAR domain and Reptin is mutually exclusive which regulates the nucleocytoplasmic shuttling of Reptin. Furthermore, Reptin is unable to bind with membrane-associated APPL proteins. These observations were further expanded by experimental approaches where we identified a novel point mutation D316N lying in the APPL1(PH) domain which resulted in a significantly reduced binding with Reptin. By luciferase assays, we observed that overexpression of APPL1(D316N) and APPL1(WT) stimulated β-catenin/TCF dependent transcriptional activity in a similar manner which suggested that binding of Reptin to APPL1 is not necessary for β-catenin dependent target gene expression. Overall, our data attempt to highlight a comparative role of APPL proteins in controlling β-catenin dependent transcription mechanism which may improve our understanding of gene regulation.

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          Author and article information

          Journal
          Comput Biol Chem
          Computational biology and chemistry
          Elsevier BV
          1476-928X
          1476-9271
          Dec 2013
          : 47
          Affiliations
          [1 ] National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan. Electronic address: sajidrwp@yahoo.co.uk.
          Article
          S1476-9271(13)00056-X
          10.1016/j.compbiolchem.2013.05.005
          23891720
          6758863e-9f63-4622-8834-71fd2e078548

          Molecular docking, PH domain, Reptin, APPL, β-Catenin, BAR domain

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