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Ancestral protein reconstruction allows the resurrection and characterization of ancient proteins based on computational analyses of sequences of modern-day proteins. Unfortunately, many protein families are highly divergent and not suitable for sequence-based reconstruction approaches. This limitation is exemplified by the antigen receptors of jawed vertebrates (B- and T-cell receptors), heterodimers formed by pairs of Ig domains. These receptors are believed to have evolved from an extinct homodimeric ancestor through a process of gene duplication and diversification; however molecular evidence has so far remained elusive. Here, we use a structural approach and laboratory evolution to reconstruct such molecules and characterize their interaction with antigen. High-resolution crystal structures of reconstructed homodimeric receptors in complex with hen-egg white lysozyme demonstrate how nanomolar affinity binding of asymmetrical antigen is enabled through selective recruitment and structural plasticity within the receptor-binding site. Our results provide structural evidence in support of long-held theories concerning the evolution of antigen receptors, and provide a blueprint for the experimental reconstruction of protein ancestry in the absence of phylogenetic evidence.
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http://dx.doi.org/10.1073/pnas.1613477114 | DOI Listing |
J Mol Biol
March 2025
Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan; International Institute for Sustainability with Knotted Chiral Meta Matter (WPI-SKCM2), Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan. Electronic address:
Isomerization of L-aspartate (L-Asp) into D-aspartate (D-Asp) occurs naturally in proteins at a rate that is much faster than that of other amino acid types. Accumulation of D-Asp is age-dependent, which could alter protein structures and, therefore, functions. Site-specific introduction of D-Asp can accelerate aggregation kinetics of a variety of proteins associated with misfolding diseases.
View Article and Find Full Text PDFNeurosci Bull
March 2025
Department of Anesthesiology and Perioperative Medicine, Department of Pain Medicine, Key Laboratory of Anesthesiology, Ministry of Education of China, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
Neuropathic pain, often featuring allodynia, imposes significant physical and psychological burdens on patients, with limited treatments due to unclear central mechanisms. Addressing this challenge remains a crucial unsolved issue in pain medicine. Our previous study, using protein kinase C gamma (PKCγ)-tdTomato mice, highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.
View Article and Find Full Text PDFCryo Letters
March 2025
International Research Group - IRG, Natal, Brazil.
Background: The skin, the largest organ in the human body, is composed of complex layers that include subcutaneous adipose tissue. Understanding the characteristics of this skin structure is essential to optimize therapeutic interventions, such as cryolipolysis, aiming for more effective and personalized results.
Objective: To evaluate the immunohistochemical effects of skin tissue in adult women undergoing cryolipolysis.
J Agric Food Chem
March 2025
MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian 116024, Liaoning, China.
Oleate hydratases (Ohys) catalyze the conversion of oleic acid (OA) to 10-()-hydroxystearic acid (10-HSA), a compound widely used in the chemical industry. However, the limited activity of Ohys has hindered their broader applications. To address this limitation, we propose a novel strategy for mining highly active Ohys through structure clustering, sequence clustering, and ancestral sequence reconstruction (SSA strategy).
View Article and Find Full Text PDFJ Biomed Mater Res A
March 2025
Department of Cytology, Institute of Developmental Biology and Biomedical Sciences, Faculty of Biology, University of Warsaw, Warsaw, Poland.
Skeletal muscle regeneration depends on satellite cells, which, in response to injury, activate, proliferate, and reconstruct damaged tissue. However, under certain conditions, such as large injuries or myopathies, this process may not be properly executed, and muscle function may be affected. Thus, pro-regenerative actions, such as the use of various factors or cells, are widely tested as a tool to improve muscle regeneration.
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