{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Biancalana M"],"funding":["NIDDK NIH HHS","NIGMS NIH HHS"],"pagination":["3469-74"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC2840449"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["107(8)"],"pubmed_abstract":["Demonstrated successes of protein design and engineering suggest significant potential to produce diverse protein architectures and assemblies beyond those found in nature. Here, we describe a new class of synthetic protein architecture through the successful design and atomic structures of water-soluble cross-beta proteins. The cross-beta motif is formed from the lamination of successive beta-sheet layers, and it is abundantly observed in the core of insoluble amyloid fibrils associated with protein-misfolding diseases. Despite its prominence, cross-beta has been designed only in the context of insoluble aggregates of peptides or proteins. Cross-beta's recalcitrance to protein engineering and conspicuous absence among the known atomic structures of natural proteins thus makes it a challenging target for design in a water-soluble form. Through comparative analysis of the cross-beta structures of fibril-forming peptides, we identified rows of hydrophobic residues (\"ladders\") running across beta-strands of each beta-sheet layer as a minimal component of the cross-beta motif. Grafting a single ladder of hydrophobic residues designed from the Alzheimer's amyloid-beta peptide onto a large beta-sheet protein formed a dimeric protein with a cross-beta architecture that remained water-soluble, as revealed by solution analysis and x-ray crystal structures. These results demonstrate that the cross-beta motif is a stable architecture in water-soluble polypeptides and can be readily designed. Our results provide a new route for accessing the cross-beta structure and expanding the scope of protein design."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["Minimalist design of water-soluble cross-beta architecture."],"pmcid":["PMC2840449"],"funding_grant_id":["T90 DK070076","R01 GM057215","T90-DK070076","R01-GM057215"],"pubmed_authors":["Makabe K","Koide S","Biancalana M"],"additional_accession":[]},"is_claimable":false,"name":"Minimalist design of water-soluble cross-beta architecture.","description":"Demonstrated successes of protein design and engineering suggest significant potential to produce diverse protein architectures and assemblies beyond those found in nature. Here, we describe a new class of synthetic protein architecture through the successful design and atomic structures of water-soluble cross-beta proteins. The cross-beta motif is formed from the lamination of successive beta-sheet layers, and it is abundantly observed in the core of insoluble amyloid fibrils associated with protein-misfolding diseases. Despite its prominence, cross-beta has been designed only in the context of insoluble aggregates of peptides or proteins. Cross-beta's recalcitrance to protein engineering and conspicuous absence among the known atomic structures of natural proteins thus makes it a challenging target for design in a water-soluble form. Through comparative analysis of the cross-beta structures of fibril-forming peptides, we identified rows of hydrophobic residues (\"ladders\") running across beta-strands of each beta-sheet layer as a minimal component of the cross-beta motif. Grafting a single ladder of hydrophobic residues designed from the Alzheimer's amyloid-beta peptide onto a large beta-sheet protein formed a dimeric protein with a cross-beta architecture that remained water-soluble, as revealed by solution analysis and x-ray crystal structures. These results demonstrate that the cross-beta motif is a stable architecture in water-soluble polypeptides and can be readily designed. Our results provide a new route for accessing the cross-beta structure and expanding the scope of protein design.","dates":{"release":"2010-01-01T00:00:00Z","publication":"2010 Feb","modification":"2025-04-18T23:15:05.414Z","creation":"2019-03-26T23:57:47Z"},"accession":"S-EPMC2840449","cross_references":{"pubmed":["20133689"],"doi":["10.1073/pnas.0912654107"]}}