HAP1 can sequester a subset of TBP in cytoplasmic inclusions via specific interaction with the conserved TBPCOREReportar como inadecuado

HAP1 can sequester a subset of TBP in cytoplasmic inclusions via specific interaction with the conserved TBPCORE - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

BMC Molecular Biology

, 8:76

First Online: 14 September 2007Received: 07 March 2007Accepted: 14 September 2007


BackgroundHuntington-s disease, spinal and bulbar muscular atrophy, and spinocerebellar ataxia 17 SCA17 are caused by expansions in the polyglutamine polyQ repeats in Huntingtin protein Htt, androgen receptor protein AR, and TATA-binding protein TBP, respectively. Htt-associated protein 1 HAP1, a component of neuronal cytoplasmic stigmoid bodies STBs, can sequester polyQ-expanded Htt and AR in STBs, thereby antagonizing formation of the nuclear aggregates associated with apoptotic neuron loss and disease progression.

ResultsClones of HAP1 were isolated from unbiased two-hybrid screens for proteins that interact with TBP. Domain mapping showed that regions between amino acids 157 and 261 and between amino acids 473 and 582 of mouse HAP1 both bind specifically to the conserved C-terminal TBPCORE domain, away from the TBP N-terminal polyQ region. When fluorescently tagged versions of HAP1 or TBP were expressed independently in COS-7, 293, or Neuro-2a cells, all TBP localized to the nucleus and all HAP1 assembled into cytoplasmic stigmoid-like bodies STLBs. When co-expressed, a portion of the TBP was assembled into the HAP1 STLBs while the remainder was localized to the nucleus. Although the TBP N terminus, including the polyQ region, was unnecessary for TBP-HAP1 interaction, in mammalian cells, removal of the TBP Qrepeat reduced the proportion of TBP that assembled into STLBs, whereas expansion of the Qrepeat had no significant affect on TBP subcellular localization.

ConclusionHAP1 can sequester a subset of TBP protein away from the nucleus; extranuclear TBP sequestration is quantitatively influenced by the TBP polyQ repeat. These results suggest HAP1 could provide protection from SCA17 neuropathology.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2199-8-76 contains supplementary material, which is available to authorized users.

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Autor: Justin R Prigge - Edward E Schmidt

Fuente: https://link.springer.com/

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