Identification of a self-association region within the SCA1 gene product, ataxin-1

Burright, Eric N.; Davidson, Jennifer D.; Duvick, Lisa A.; Koshy, Beena; Zoghbi, Huda Y.; Orr, Harry T.

doi:10.1093/hmg/6.4.513

Cited by 59 publications

(42 citation statements)

References 16 publications

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“…We prepared protein extracts from mouse brain tissue as previously described (4). Briefly tissues were homogenized in protein extraction buffer containing 100 mM Tris, pH 6.8, 2% sodium dodecyl sulfate (SDS), 25 mM dithiothreitol, and protease inhibitors (Complete; Roche Molecular Biochemicals).…”

Section: Methodsmentioning

confidence: 99%

Generation and Characterization of LANP/pp32 Null Mice

Opal

Garcı́a

McCall

et al. 2004

Molecular and Cellular Biology

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The leucine-rich acidic nuclear protein (LANP) belongs to a family of evolutionarily conserved proteins that are characterized by an amino-terminal domain rich in leucine residues followed by a carboxy-terminal acidic tail. LANP has been implicated in the regulation of a variety of cellular processes including RNA transport, transcription, apoptosis, vesicular trafficking, and intracellular signaling. Abundantly expressed in the developing cerebellum, this protein has also been hypothesized to play a role in cerebellar morphogenesis. LANP has been implicated in disease biology as well, both as a mediator of toxicity in spinocerebellar ataxia type 1 and as a tumor suppressor in cancers of the breast and prostate. To better understand the function of this multifaceted protein, we have generated mice lacking LANP. Surprisingly, these mice are viable and fertile. In addition we could not discern any derangements in any of the major organ systems, including the nervous system, which we have studied in detail. Overall our results point to a functional redundancy of LANP's function, most likely provided by its closely related family members.Leucine-rich acidic nuclear protein (LANP or pp32 [for phosphoprotein with a molecular mass of 32 kDa]) is a member of the leucine-rich family of proteins (16-18). These proteins are involved in a variety of pathways including signaling, protein degradation, cytoskeletal dynamics, and morphogenesis, presumably based on the ability of the leucine-rich repeat (LRR) domains to serve as adapter sites for protein-protein interactions.For LANP, the hydrophobic LRRs reside in its N-terminal domain, giving LANP a globular head domain. The C-terminal domain, on the other hand, is extended and hydrophilic, engaging interactors by virtue of its ionic interactions (23,27,30,31).Several proteins have extensive homology to LANP, both in displaying LRRs in their N terminal domains and in demonstrating extended acidic tail domains. These proteins represent true LANP family members that have probably arisen by gene duplication. The nomenclature of LANP family members is confusing because the same protein has been given more than one name based on the context of isolation. Thus APRIL, an acronym derived from A protein rich in leucines, is also known as PAL-31, for proliferation-associated leucine-rich protein, MW 31kDa, and SSP-29, for silver-stainable protein with a molecular mass of 29 kDa (24,25,41). CPD1 (cerebellar postnatal development protein 1), another LANP family member, has been called LANP-like protein (LANP-L) (21, 28). Two human homologues of LANP/pp32 have been called pp32r1 and pp32r2 to signify that they are related (14,15). Besides having homology with these proteins, LANP family members also have limited homology to template-activating factor (TAF) proteins, TAF-1 alpha and beta (the latter being the product of the SET oncogene). The TAF-1 proteins, like the LANP family members, demonstrate long acidic C-terminal domains but, unlike LANP, do not display LRRs in their Nterminal doma...

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Section: Methodsmentioning

confidence: 99%

Generation and Characterization of LANP/pp32 Null Mice

Opal

Garcı́a

McCall

et al. 2004

Molecular and Cellular Biology

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“…A highly conserved ATXN1/HBP1 (AXH) domain in ATXN1, which is required for SCA1 pathogenesis (Tsuda et al 2005), interacts with an N-terminal region of CIC (Lam et al 2006). Furthermore, the AXH domain is required for ATXN1 self-association, which is also shown by the crystal structure of the AXH domain alone (Burright et al 1997;Chen et al 2004). Although ATXN1 interacts with several cellular partners and regulates their activities, the biochemical properties of ATXN1 and the molecular mechanism mediating complex formation of ATXN1 with a protein such as CIC are still not well understood.…”

mentioning

confidence: 88%

Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua

Kim

Zoghbi

et al. 2013

Genes Dev.

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Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by polyglutamine expansion in Ataxin-1 (ATXN1). ATXN1 binds to the transcriptional repressor Capicua (CIC), and the interaction plays a critical role in SCA1 pathogenesis whereby reducing CIC levels rescues SCA1-like phenotypes in a mouse model. The ATXN1/HBP1 (AXH) domain of ATXN1 mediates its homodimerization as well as the interaction with CIC. Here, we present the crystal structure of ATXN1's AXH domain bound to CIC and show that the binding pocket of the AXH domain to CIC overlaps with the homodimerization pocket of the AXH domain. Thus, the binding to CIC disrupts the homodimerization of ATXN1. Furthermore, the binding of CIC reconfigures the complex to allow another form of dimerization mediated by CIC, showing the intricacy of protein complex formation and reconfiguration by ATXN1 and CIC. Identifying the surfaces mediating the interactions between CIC and ATXN1 reveals a critical role for CIC in the reconfiguration of the AXH dimers and might provide insight into ways to target the ATXN1/CIC interactions to modulate SCA1 pathogenesis.

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“…Also, an increase in the length of the polyglutamine tracts could influence dimer formation and selfaggregation, leading to precipitation [Perutz, 1996]. The SCA2 protein has been shown to form a dimer, but in this case polyglutamine tracts are not involved in dimer formation [Burright et al, 1997]. In the case of the MJD protein, differences in the number of glutamine residues in monomers may result in the production of asymmetric dimers which could alter normal function.…”

Section: Discussionmentioning

confidence: 99%

Variation at the MJD locus in the major psychoses

et al. 1998

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Expansion of triplet repeats has been seen to underlie several disorders that manifest anticipation. Clinical evidence suggests that anticipation occurs in the major psychoses. We studied the distribution of repeat sizes at the Machado-Joseph disease (MJD) locus in a group of patients with the major psychoses. We did not find any large expansions, though 2 patients had alleles that were two repeats larger than in our controls. The difference in allele sizes was larger in the patient sample as compared to the controls. The effect of such large differences might be of functional significance.

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Identification of a self-association region within the SCA1 gene product, ataxin-1

Cited by 59 publications

References 16 publications

Generation and Characterization of LANP/pp32 Null Mice

Generation and Characterization of LANP/pp32 Null Mice

Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua

Variation at the MJD locus in the major psychoses

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