Disease-Associated Polyglutamine Stretches in Monomeric Huntingtin Adopt a Compact Structure

Peters‐Libeu, Clare; Miller, Jason; Rutenber, Earl; Newhouse, Yvonne M.; Krishnan, Preethi; Cheung, Katherine; Hatters, Danny M.; Brooks, Elizabeth D.; Widjaja, Kartika; Tran, Tina; Mitra, Siddhartha; Arrasate, Montserrat; Mosquera, Luis A.; Taylor, D.; Weisgraber, Karl H.; Finkbeiner, Steven

doi:10.1016/j.jmb.2012.01.034

Cited by 52 publications

(78 citation statements)

References 57 publications

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“…According to this model, the postulated pathologic conformation could be directly toxic or it could alter interactions between mutant huntingtin and its binding partners; in either case, the pathologic conformation could be targeted for drug design. Support for this model was provided by studies of the anti-polyQ antibody 3B5H10, which was reported to recognize a single epitope representing a distinct pathologic conformation of soluble expanded polyQ [8, 9]. In these studies, 3B5H10 IgG preferentially bound to expanded polyQ, and a two-stranded β-hairpin conformation of polyQ was modeled into the predicted polyQ-binding groove of the 3B5H10 Fab structure [9].…”

Section: Introductionmentioning

confidence: 99%

Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1

Owens

New

West

et al. 2015

Journal of Molecular Biology

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Huntington’s disease (HD) is caused by expansion of a polyglutamine (polyQ) repeat in the huntingtin protein. A structural basis for the apparent transition between normal and disease-causing expanded polyQ repeats of huntingtin is unknown. The ‘linear lattice’ model proposed random-coil structures for both normal and expanded polyQ in the preaggregation state. Consistent with this model, the affinity and stoichiometry of the anti-polyQ antibody MW1 increased with the number of glutamines. An opposing ‘structural toxic threshold’ model proposed a conformational change above the pathogenic polyQ threshold resulting in a specific toxic conformation for expanded polyQ. Support for this model was provided by the anti-polyQ antibody 3B5H10, which was reported to specifically recognize a distinct pathologic conformation of soluble expanded polyQ. To distinguish between these models, we directly compared binding of MW1 and 3B5H10 to normal and expanded polyQ repeats within huntingtin exon 1 fusion proteins. We found similar binding characteristics for both antibodies. First, both antibodies bound to normal, as well as expanded, polyQ in huntingtin exon 1 fusion proteins. Second, an expanded polyQ tract contained multiple epitopes for antigen-binding fragments (Fabs) of both antibodies, demonstrating that 3B5H10 does not recognize a single epitope specific to expanded polyQ. Finally, small angle X-ray scattering and dynamic light scattering revealed similar binding modes for MW1 and 3B5H10 Fab-huntingtin exon 1 complexes. Together, these results support the linear lattice model for polyQ binding proteins, suggesting that the hypothesized pathologic conformation of soluble expanded polyQ is not a valid target for drug design.

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Section: Introductionmentioning

confidence: 99%

Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1

Owens

New

West

et al. 2015

Journal of Molecular Biology

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“…So far, structural studies on htt exon1 constructs in solution have used computational10 or low‐resolution approaches,10, 11, 12, 13 and focused mainly on the overall properties of the poly‐Q tract. Unfortunately, these studies have reported contradictory observations regarding the conformational preferences of the HR.…”

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confidence: 99%

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats

et al. 2018

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Homorepeat (HR) proteins are involved in key biological processes and multiple pathologies, however their high‐resolution characterization has been impaired due to their homotypic nature. To overcome this problem, we have developed a strategy to isotopically label individual glutamines within HRs by combining nonsense suppression and cell‐free expression. Our method has enabled the NMR investigation of huntingtin exon1 with a 16‐residue polyglutamine (poly‐Q) tract, and the results indicate the presence of an N‐terminal α‐helix at near neutral pH that vanishes towards the end of the HR. The generality of the strategy was demonstrated by introducing a labeled glutamine into a pathological version of huntingtin with 46 glutamines. This methodology paves the way to decipher the structural and dynamic perturbations induced by HR extensions in poly‐Q‐related diseases. Our approach can be extended to other amino acids to investigate biological processes involving proteins containing low‐complexity regions (LCRs).

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“…It is thought that expansion of the polyglutamine region leads to pathological protein self-aggregation with a cross-β-strand structure similar to β-amyloid. A crystal structure of 3B5H10 F ab at 0.19 nm resolution revealed enrichment of solvent-accessible aromatic residues in the H-chain CDRs, facilitating glutamine binding [20]. In fact, 30 % of the H-chain CDRs were aromatic, compared to 9 % in 100 closest homologues.…”

Section: Current Perspectivesmentioning

confidence: 99%

“…In fact, 30 % of the H-chain CDRs were aromatic, compared to 9 % in 100 closest homologues. In a second polyglutamine-recognizing antibody, MW1, this number is 39 % [20]. Upon recognition of the polygluatmine epitope, a 3° rotation between the H-and L chains results in a linear groove that accommodates the antigen.…”

Section: Current Perspectivesmentioning

confidence: 99%

Structural aspects of molecular recognition in the immune system. Part I: Acquired immunity (IUPAC Technical Report)

Templeton

Moehle

2014

Pure and Applied Chemistry

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Humoral immunity allows the body to mount a defense against pathogens and foreign substances, and to respond with memory to subsequent exposures. The molecular participants may also recognize selfstructures, leading to attack on the body and autoimmune disease. The main players in humoral immunity are antibody-producing B lymphocytes, and several classes of T lymphocytes. This review deals with the molecular details of recognition of antigens by soluble antibodies, and of substances presented to receptors on the surfaces of T cells (TCRs). The prototype antibody consists of a dimer of dimers, two heavy (H) chains and two light (L) chains, with antigen recognition capacity lying in variable "head" regions of an H-L pair. Most crystallographic studies are done with this substructure, called a F ab fragment, bound in a soluble antigen complex. Homologous to this arrangement, the prototype TCR consists of two chains (α and β) that complex not soluble antigen, but usually a short peptide or other small molecule presented by proteins of the major histocompatibility complex. In each case a general background on the historical development of understanding the molecular recognition interface is given, followed by a number of examples of crystal structures from the recent literature that have allowed us to refine our understanding of the complex recognition process. Variations on the prototypical structures are also considered. The spectrum of recognition strategies involves interplay of lock-and-key with flexibility, varying degrees of entropic and enthalpic contributions, surface shaping by entrapped water molecules, and combinations of stabilizing hydrogen bonding, electrostatic interactions, salt bridging, and van der Waals forces. Preeminent in the recent literature are details of antibody binding to influenza A and human immunodeficiency viral antigens. Both viral antigens and attempts to understand autoimmunity are prominent in the recent TCR literature.

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Disease-Associated Polyglutamine Stretches in Monomeric Huntingtin Adopt a Compact Structure

Cited by 52 publications

References 57 publications

Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1

Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats

Structural aspects of molecular recognition in the immune system. Part I: Acquired immunity (IUPAC Technical Report)

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