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| Open AccessDeep mutational scanning reveals a correlation between degradation and toxicity of thousands of aspartoacylase variants
The details of how the protein folding and degradation systems collaborate to combat potentially toxic non-native proteins are unknown. Here the authors perform systematic studies of missense and nonsense variants of the cytosolic aspartoacylase, ASPA, where loss-of-function variants are linked to Canavan disease.
- Martin Grønbæk-Thygesen
- , Vasileios Voutsinos
- & Rasmus Hartmann-Petersen
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Article
| Open AccessLoCoHD: a metric for comparing local environments of proteins
The techniques available for comparing protein structures do not focus directly on the chemical nature of residue environments. Here, authors describe a computational method that can capture both the spatial and chemical dissimilarities of residue surroundings.
- Zsolt Fazekas
- , Dóra K. Menyhárd
- & András Perczel
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| Open AccessPharmacological inhibition of α-synuclein aggregation within liquid condensates
Aggregated forms of α-synuclein are characteristic of Parkinson’s disease. Here the authors show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules: the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein primary nucleation in the aggregation process.
- Samuel T. Dada
- , Zenon Toprakcioglu
- & Michele Vendruscolo
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| Open AccessProtein mimetic 2D FAST rescues alpha synuclein aggregation mediated early and post disease Parkinson’s phenotypes
The aggregation of the neuronal protein α-Synuclein is associated with the onset of Parkinson’s disease. Here the authors report a two-dimensional Fragment Assisted Structure-based technique to find antagonists of α-Synuclein aggregation and show its promise for identifying lead therapeutics for Parkinson’s disease.
- Nicholas H. Stillman
- , Johnson A. Joseph
- & Sunil Kumar
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| Open AccessTracing genetic diversity captures the molecular basis of misfolding disease
Pei et al. applied Gaussian process-based machine learning to capture dynamic spatial covariance relationships managed by proteostasis to mediate cooperative folding on a residue basis as a standard model for precision disease management.
- Pei Zhao
- , Chao Wang
- & William E. Balch
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Article
| Open AccessRapid evolutionary change in trait correlations of single proteins
Trait correlations impact evolvability as selection on one trait can influence others. Here, the authors examine trait correlation in two proteins, a fluorescent protein & an antibiotic resistance enzyme, observing rapid evolution of trait correlations through changes in the biophysical properties of these proteins.
- Pouria Dasmeh
- , Jia Zheng
- & Andreas Wagner
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Article
| Open AccessDynamics of DNA damage-induced nuclear inclusions are regulated by SUMOylation of Btn2
Maintaining a healthy nuclear proteome during DNA damage is important but its regulation is poorly understood. The authors here show that a SUMO modification of the small heat shock protein Btn2 regulates yeast nuclear protein sequestration during stress.
- Arun Kumar
- , Veena Mathew
- & Peter C. Stirling
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Article
| Open AccessThe assembly platform FimD is required to obtain the most stable quaternary structure of type 1 pili
Type 1 pili are crucial cell surface bacterial virulence factors. Here, the authors show that FimD is required to assemble the most stable quaternary pilus structure by ensuring that the resulting protein polymer is free of structural defects.
- Dawid S. Zyla
- , Thomas Wiegand
- & Rudi Glockshuber
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Article
| Open AccessHalogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus
Modulating amyloid protein phase separation and fibrilization may help in addressing neurodegenerative diseases. This study demonstrates that halogen-doped graphene quantum dots can modulate these processes in TDP-43 in both nucleus and cytoplasm.
- Hong Zhang
- , Huazhang Guo
- & Bin Dai
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Article
| Open AccessHairpin trimer transition state of amyloid fibril
Amyloid fibrils are ordered protein assemblies implicated in neurodegenerative disease. Here the authors show that hairpin trimers can be transition states of fibril nucleation, explaining how different fibril isoforms may arise from alternative nucleation sites.
- Levent Sari
- , Sofia Bali
- & Milo M. Lin
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Article
| Open AccessPhosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures
Here, the authors use cryo-EM to show that phosphorylating or O-GlcNAcylating α-synuclein on serine 87 leads to the formation of two distinct fibril structures. Both structures display reduced neurotoxicity and propagation activity.
- Jinjian Hu
- , Wencheng Xia
- & Yan-Mei Li
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Article
| Open AccessDiverging co-translational protein complex assembly pathways are governed by interface energy distribution
Protein complex assembly can occur co-translationally. Here, the authors uncover diverging assembly pathways and hotspot disruptions in N-terminal acetyltransferases, enzymes implicated in neurodegenerative diseases. Their model predicts co-translational assembly based on interface energy distribution.
- Johannes Venezian
- , Hagit Bar-Yosef
- & Ayala Shiber
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Article
| Open AccessHTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer’s disease. Here the authors report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
- Sheng Chen
- , Anuradhika Puri
- & Meredith E. Jackrel
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Article
| Open AccessA Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
- Hasier Eraña
- , Cristina Sampedro-Torres-Quevedo
- & Joaquín Castilla
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Article
| Open AccessBioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2
The main protease (Mpro) plays a crucial role in the replication of SARS-CoV-2, thereby making it an attractive target for COVID-19 treatment. Here, the authors develop a colorimetric screening platform for discovering Mpro inhibitors using engineered amyloid peptide-based nanocomplexes.
- Dongtak Lee
- , Hyo Gi Jung
- & Dae Sung Yoon
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Article
| Open AccessAlternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function.
- Rosa Antón
- , Miguel Á. Treviño
- & Javier Oroz
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Article
| Open AccessAggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa
Mutations in rhodopsin can cause the receptor to aggregate, however, it is unclear whether this molecular defect underlies the retinal degeneration in autosomal dominant retinitis pigmentosa. Here, the authors show the potential for rhodopsin aggregates to play a role in retinal degeneration.
- Sreelakshmi Vasudevan
- , Subhadip Senapati
- & Paul S.–H. Park
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Article
| Open AccessSEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex
The importance of the SEL1L-HRD1 interaction in vivo was unclear. Here, authors reported that SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex by recruiting the E2 enzyme UBE2J1 and DERLIN to HRD1.
- Liangguang Leo Lin
- , Huilun Helen Wang
- & Ling Qi
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Article
| Open AccessReduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase
Neurodegenerative diseases often co-accumulate several disease-associated proteins. Here, the authors show that reduction of progranulin, a protein associated with TDP-43, also increases accumulation of tau and a-synuclein via glucocerebrosidase.
- Hideyuki Takahashi
- , Sanaea Bhagwagar
- & Stephen M. Strittmatter
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| Open AccessChp1 is a dedicated chaperone at the ribosome that safeguards eEF1A biogenesis
Here the authors discover a dedicated ribosome-associated chaperone, Chp1, that assists in the challenging biogenesis of eukaryotic translation elongation factor 1A (eEF1A) by cotranslationally stabilizing the growing GTPase domain of eEF1A.
- Melania Minoia
- , Jany Quintana-Cordero
- & Claes Andréasson
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| Open AccessCryo-EM structures of lipidic fibrils of amyloid-β (1-40)
Alzheimer’s plaques contain a high amount of Aβ fibrils and a high concentration of lipids. The authors determined structures of Aβ40 fibrils grown in the presence of lipids, revealing high-resolution details of potentially disease-relevant fibril-lipid interactions.
- Benedikt Frieg
- , Mookyoung Han
- & Gunnar F. Schröder
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Article
| Open AccessProtein thermal sensing regulates physiological amyloid aggregation
Cells form non-pathological amyloids to survive stressful conditions. Marijan et al. show that heat shock-induced aggregation is self-regulated by protein stability, with high-ordered motifs acting as thermo-switches that control amyloidogenesis.
- Dane Marijan
- , Evgenia A. Momchilova
- & Timothy E. Audas
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| Open AccessAmyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Alzheimer’s Disease (AD) is commonly preceded by a prodromal period. Here, the authors report the presence of large plasma Aβ aggregates from patients with mild cognitive impairment, which associate with low level AD-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes.
- Kristian Juul-Madsen
- , Peter Parbo
- & Thomas Vorup-Jensen
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| Open AccessA structural vista of phosducin-like PhLP2A-chaperonin TRiC cooperation during the ATP-driven folding cycle
Proper cellular proteostasis requires a network of the chaperonin TRiC/CCT with cochaperones prefoldin (PFD) and phosducin-like proteins (PhLPs) to facilitate the folding of essential eukaryotic proteins. Here, the authors characterized the ATP-driven cycle of TRiC-PFD-PhLP2A interaction using cryoEM and biochemical analyses.
- Junsun Park
- , Hyunmin Kim
- & Soung-Hun Roh
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Article
| Open AccessFolding pathway of a discontinuous two-domain protein
Here, using single molecule FRET, the unfolding and folding of a discontinuous two-domain protein was studied. The authors find that a dynamic, intermediate population entropically limits the rate of folding while the order of domain folding is kept in a slow-folding mutant.
- Ganesh Agam
- , Anders Barth
- & Don C. Lamb
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Article
| Open AccessStructure of the M. tuberculosis DnaK−GrpE complex reveals how key DnaK roles are controlled
Cryo-EM analysis reveals that the GrpE dimer of M. tuberculosis undergoes ratcheting motions when bound to an intact DnaK, thereby allosterically regulating DnaK’s nucleotide exchange and substrate release.
- Xiansha Xiao
- , Allison Fay
- & Huilin Li
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Article
| Open AccessProteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis
The nature of SEL1L-HRD1 ERAD substrates remains unclear. Here, the authors identified ~100 endogenous substrates, and showed that SEL1L-HRD1 ERAD is indispensable for the activity of GPI transamidase complex and the biogenesis of GPI-anchored proteins.
- Xiaoqiong Wei
- , You Lu
- & Ling Qi
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Article
| Open AccessStructural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy
In this work, the authors report Cryo-EM imaging revealing diversity in amyloid fibril structures among ATTR patients with the same genetic mutation I84S. Further study is warranted to grasp the implications in ATTR amyloidosis pathology.
- Binh An Nguyen
- , Virender Singh
- & Lorena Saelices
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| Open AccessCryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils
This study presents the cryo-EM structures of polymorphic TDP-43-derived amyloid fibrils that share a common fibril protein conformation constituting an amyloid key motif. The obtained results provide a possible mechanistic explanation for the formation of this motif in amyloid fibrils.
- Kartikay Sharma
- , Fabian Stockert
- & Marcus Fändrich
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Article
| Open AccessNuclear Hsp104 safeguards the dormant translation machinery during quiescence
During aging, proteins are damaged and can misfold, compromising cellular viability. Here, Kohler et al. uncover how aging cells maintain fitness by redirecting the protein repair factor Hsp104 to the nucleus in response to metabolic cues.
- Verena Kohler
- , Andreas Kohler
- & Sabrina Büttner
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Article
| Open AccessDynamic stability of Sgt2 enables selective and privileged client handover in a chaperone triad
Newly synthesized tail-anchored membrane proteins (TAs) are relayed in a chaperone triad, Hsp70, Sgt2, and Get3, for delivery to the endoplasmic reticulum. Here, the authors show how the conformational dynamics of the cochaperone Sgt2 generates a decision point to enable efficient and selective TA targeting.
- Hyunju Cho
- , Yumeng Liu
- & Shu-ou Shan
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Article
| Open AccessCompetition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller
Here, the relationship between unfolding and amyloid aggregation of glaucoma-associated myocilin is probed, showing that myocilin is not at equilibrium and pathogenic aggregation competes directly with unfolding.
- Emily G. Saccuzzo
- , Mubark D. Mebrat
- & Raquel L. Lieberman
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Article
| Open AccessPrion protein conversion at two distinct cellular sites precedes fibrillisation
In this work, the authors investigated the cellular mode of prion propagation. The report that proteopathic seeds of abnormal PrP are N-terminally truncated and detected within minutes after infection. These seeds reach the plasma membrane by regulated secretory pathways where phenotypically distinct fibril-like PrP aggregates are formed with a lag of 24 h after infection.
- Juan Manuel Ribes
- , Mitali P. Patel
- & Peter-Christian Klöhn
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| Open AccessExcess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy
The prion protein PrPC is known to play a role in skeletal muscle development and physiology, including in myopathy. Here, the authors report that excess PrPC binds microRNAs that enhance its aggregation, which inhibits autophagy in muscle cells.
- Jing Tao
- , Yanping Zeng
- & Yi Liang
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Article
| Open AccessProgrammable de novo designed coiled coil-mediated phase separation in mammalian cells
Membraneless liquid compartments based on phase-separating biopolymers have been observed in diverse cell types and attributed to weak multivalent interactions predominantly based on intrinsically disordered domains. Here the authors design protein liquid condensates from tunable concatenated coiled-coil dimer modules, unraveling the principles for coexisting condensates, chemical regulation, formation from either one or two polypeptide components in mammalian cells.
- Maruša Ramšak
- , Dominique A. Ramirez
- & Roman Jerala
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Article
| Open AccessCommon transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis
Hereditary ATTR amyloidosis has diverse disease manifestations. Using cryo-EM it was possible to reveal, that the phenotypic variations arise from the circumstances under which the amyloid fibrils are formed, rather than from different fibril morphologies.
- Maximilian Steinebrei
- , Julian Baur
- & Marcus Fändrich
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Article
| Open AccessCis-trans isomerization of peptoid residues in the collagen triple-helix
The cis-peptide bond is rare in natural proteins and its impact on protein folding is elusive. Here the authors break the conventional understanding that cis-amide-favoring residues destabilize proteins, elucidate the principles of peptoid cis-trans isomerization in collagen folding, and showcase the use of cis-amide-favoring residues in building programmable and functional peptidomimetics.
- Rongmao Qiu
- , Xiaojing Li
- & Yang Li
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Article
| Open AccessSpatially resolved mapping of proteome turnover dynamics with subcellular precision
Mapping protein turnover dynamics with subcellular precision is crucial for understanding cell physiology and pathology. Here, the authors leveraged APEX2-mediated proximity labeling to develop prox-SILAC methods to profile protein turnover rates in the mitochondria and endoplasmic reticulum.
- Feng Yuan
- , Yi Li
- & Peng Zou
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Article
| Open AccessStructure and function of the EA1 surface layer of Bacillus anthracis
S-layers form continuous protein lattices on the surface of bacteria. Here, authors use S-layer depolymerizing nanobodies to solve the structure of the EA1 S-layer in the pathogen Bacillus anthracis and show its role as cell wall supportive structure”
- Adrià Sogues
- , Antonella Fioravanti
- & Han Remaut
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Article
| Open AccessDNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones
Here the authors characterize DNAJB6 mutants found in LGMDD1 patients. They show that these mutants retain aggregation-prevention activity, but have impaired regulation of Hsp70 binding, uncontrollably recruiting Hsp70s, depleting the chaperone levels and disrupting proteostasis.
- Meital Abayev-Avraham
- , Yehuda Salzberg
- & Rina Rosenzweig
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Article
| Open AccessFolding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling
The conformational biogenesis of multi-domain ABC-transporters is poorly understood. Here the authors show the critical role of dynamic allosteric coupling networks, its perturbation and restoration in CFTR folding, misfolding, and pharmacological rescue, respectively.
- Naoto Soya
- , Haijin Xu
- & Gergely L. Lukacs
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Article
| Open AccessFood amyloid fibrils are safe nutrition ingredients based on in-vitro and in-vivo assessment
Food protein amyloid fibrils have superior properties but due to safety concerns, have not yet been used in foods. In-vitro and in-vivo studies here show that upon digestion they are safe and can be used as potential ingredients for human nutrition.
- Dan Xu
- , Jiangtao Zhou
- & Raffaele Mezzenga
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Article
| Open AccessDe novo design of knotted tandem repeat proteins
This study reports the successful de novo design of a trefoil knotted protein fold for which the crystal structure agrees closely with the intended trefoil knot topology.
- Lindsey A. Doyle
- , Brittany Takushi
- & Philip Bradley
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Article
| Open AccessAccurate prediction of protein folding mechanisms by simple structure-based statistical mechanical models
Predicting how proteins fold into specific native structures remains challenging. Here, the authors develop a simple physical model that accurately predicts protein folding mechanisms, paving the way for solving the folding process component of the protein folding problem.
- Koji Ooka
- & Munehito Arai
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Article
| Open AccessYTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner
YTHDF2 has been extensively studied as an m6A-related RNA metabolism. Here, the authors show that YTHDF2 also contributes to protein homeostasis in an m6A-independent manner by promoting the formation of aggresomes through its interaction with UPF1.
- Hyun Jung Hwang
- , Tae Lim Park
- & Yoon Ki Kim
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Article
| Open AccessSingle-chain dimers from de novo immunoglobulins as robust scaffolds for multiple binding loops
Here the authors describe principles for de novo designing single-chain immunoglobulin dimers with interfaces diverging from those seen in antibodies, showing enhanced stability and both robustness and modularity for harboring multiple functional loops.
- Jorge Roel-Touris
- , Marta Nadal
- & Enrique Marcos
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Article
| Open AccessC3N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer’s disease
In this work, the authors report the utilization of nano-inhibito C3N nanodots to inhibit Aβ peptides aggregation and fibrils disassembly, and show how they induce a cognitive enhancement in treated AD mice.
- Xiuhua Yin
- , Hong Zhou
- & Ruhong Zhou
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Article
| Open AccessExploiting the aggregation propensity of beta-lactamases to design inhibitors that induce enzyme misfolding
Here the authors show that beta-lactamase have an intrinsic aggregation propensity that can be exploited to inactivate these enzymes that mediate antibiotic resistance, using peptides that are based on aggregation prone regions in the sequence of the beta-lactamase.
- Ladan Khodaparast
- , Laleh Khodaparast
- & Joost Schymkowitz
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Article
| Open AccessEvolutionary selection of proteins with two folds
Most globular proteins are selected to fold into one unique structure. Schafer and Porter demonstrate that some proteins are selected to assume two stable folds; they leverage this information to predict two structures from one sequence.
- Joseph W. Schafer
- & Lauren L. Porter