Micro-electron diffraction structure of the aggregation-driving N terminus of Drosophila neuronal protein Orb2A reveals amyloid-like β-sheets

Bowler, Jeannette T.; Sawaya, M.R.; Boyer, David R.; Cascio, Duilio; Bali, Manya; Eisenberg, David

doi:10.1016/j.jbc.2022.102396

Cited by 4 publications

(1 citation statement)

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“…To the best of our knowledge, this is the first experimental evidence that resolves the structures of multiple heterogeneous conformations within a β sheet peptide homoassembly. It is acknowledged that most β sheet assembly systems are difficult to crystallize, suggesting a lack of highly synchronized structures in their assemblies, i.e., the presence of entropy ( 41 , 42 ). Beyond β strands, future efforts will seek to study the conformational substate ensembles of intrinsically disordered proteins and protein regions that display structural flexibility.…”

Section: Discussionmentioning

confidence: 99%

Single-molecule visualization determines conformational substate ensembles in β-sheet–rich peptide fibrils

Zhang,

Wang,

Liu

et al. 2023

Sci. Adv.

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An understanding of protein conformational ensembles is essential for revealing the underlying mechanisms of interpeptide recognition and association. However, experimentally resolving multiple simultaneously existing conformational substates remains challenging. Here, we report the use of scanning tunneling microscopy (STM) to analyze the conformational substate ensembles of β sheet peptides with a submolecular resolution (in-plane <2.6 Å). We observed ensembles of more than 10 conformational substates (with free energy fluctuations between several k B T s) in peptide homoassemblies of keratin (KRT) and amyloidal peptides (−5Aβ42 and TDP-43 341–357). Furthermore, STM reveals a change in the conformational ensemble of peptide mutants, which is correlated with the macroscopic properties of peptide assemblies. Our results demonstrate that the STM-based single-molecule imaging can capture a thorough picture of the conformational substates with which to build an energetic landscape of interconformational interactions and can rapidly screen conformational ensembles, which can complement conventional characterization techniques.

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Section: Discussionmentioning

confidence: 99%