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Nuclear Magnetic Resonance Studies of Polyglutamine's Misfolded Conformation in the Aggregated State
Author(s) -
Wel Patrick
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.881.6
Subject(s) - neurodegeneration , huntingtin , protein folding , polyglutamine tract , biophysics , chemistry , nuclear magnetic resonance spectroscopy , protein aggregation , huntingtin protein , protein structure , fibril , folding (dsp implementation) , context (archaeology) , mutant , biochemistry , biology , stereochemistry , medicine , paleontology , disease , engineering , pathology , electrical engineering , gene
Polyglutamine sequence elements are found in various seemingly unrelated proteins, in which they appear to function as semi‐flexible linkers between protein domains. Based on structural and biophysical studies, this semi‐flexible state is functionally important and reflective of a lack of well‐defined secondary structure. An interesting, but poorly understood aspect of these functionally disordered motifs is that they are prone to misfolding as they pass a certain threshold length. This misfolding modifies the flexibility and conformation of the linker. The misfolded proteins exert cytotoxic effects, leading to neurodegeneration in a family of polyglutamine expansion diseases that include Huntington's Disease and several hereditary ataxias. Misfolding of mutant proteins is often accompanied with the formation of oligomeric and fibrillar species, which are thought to cause or modulate the cellular toxicity. We have employed magic‐angle‐spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy to elucidate the molecular structure of misfolded proteins. Our use of multidimensional MAS NMR experiments on various polyglutamine‐ and huntingtin‐based fibrils yields site‐specific structural and dynamic measurements that constrain the assembly and structure of the fibrillar core. These results provide insights on the β‐sheet‐based fibrillar structure, and reveal a remarkable conservation of structural features among different polyglutamine constructs, seemingly independent of aggregation kinetics and protein context. These MAS NMR results refine our understanding of the misfolding behavior of expanded polyglutamine and complement experimental and computational studies of the natively disordered protein domains.