András Láng, Imre Jákli, Kata Nóra Enyedi, Gábor Mező, Dóra K Menyhárd, András Perczel
{"title":"非通路3d结构提供了对自发Asn/Asp异构化的保护:屏蔽蛋白质的阿喀琉斯之踵。","authors":"András Láng, Imre Jákli, Kata Nóra Enyedi, Gábor Mező, Dóra K Menyhárd, András Perczel","doi":"10.1017/S003358351900009X","DOIUrl":null,"url":null,"abstract":"<p><p>Spontaneous deamidation prompted backbone isomerization of Asn/Asp residues resulting in - most cases - the insertion of an extra methylene group into the backbone poses a threat to the structural integrity of proteins. Here we present a systematical analysis of how temperature, pH, presence of charged residues, but most importantly backbone conformation and dynamics affect isomerization rates as determined by nuclear magnetic resonance in the case of designed peptide-models. We demonstrate that restricted mobility (such as being part of a secondary structural element) may safeguard against isomerization, but this protective factor is most effective in the case of off-pathway folds which can slow the reaction by several magnitudes compared to their on-pathway counterparts. We show that the geometric descriptors of the initial nucleophilic attack of the isomerization can be used to classify local conformation and contribute to the design of stable protein drugs, antibodies or the assessment of the severity of mutations.</p><p><p>At any –Asn/AspGly– sites in proteins a spontaneous backbone isomerization occurs within days under physiological conditions leading to various forms of proteopathy. This unwanted transformation especially harmful to long-lived proteins (e.g. hemoglobin and crystallins), can be slowed down, though never stopped, by a rigid three-dimensional protein fold, if it can delay in the conformational maze, on-pathway intermediates from occurring.</p>","PeriodicalId":20828,"journal":{"name":"Quarterly Reviews of Biophysics","volume":"53 ","pages":"e2"},"PeriodicalIF":7.2000,"publicationDate":"2020-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1017/S003358351900009X","citationCount":"1","resultStr":"{\"title\":\"Off-pathway 3D-structure provides protection against spontaneous Asn/Asp isomerization: shielding proteins Achilles heel.\",\"authors\":\"András Láng, Imre Jákli, Kata Nóra Enyedi, Gábor Mező, Dóra K Menyhárd, András Perczel\",\"doi\":\"10.1017/S003358351900009X\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Spontaneous deamidation prompted backbone isomerization of Asn/Asp residues resulting in - most cases - the insertion of an extra methylene group into the backbone poses a threat to the structural integrity of proteins. Here we present a systematical analysis of how temperature, pH, presence of charged residues, but most importantly backbone conformation and dynamics affect isomerization rates as determined by nuclear magnetic resonance in the case of designed peptide-models. We demonstrate that restricted mobility (such as being part of a secondary structural element) may safeguard against isomerization, but this protective factor is most effective in the case of off-pathway folds which can slow the reaction by several magnitudes compared to their on-pathway counterparts. We show that the geometric descriptors of the initial nucleophilic attack of the isomerization can be used to classify local conformation and contribute to the design of stable protein drugs, antibodies or the assessment of the severity of mutations.</p><p><p>At any –Asn/AspGly– sites in proteins a spontaneous backbone isomerization occurs within days under physiological conditions leading to various forms of proteopathy. This unwanted transformation especially harmful to long-lived proteins (e.g. hemoglobin and crystallins), can be slowed down, though never stopped, by a rigid three-dimensional protein fold, if it can delay in the conformational maze, on-pathway intermediates from occurring.</p>\",\"PeriodicalId\":20828,\"journal\":{\"name\":\"Quarterly Reviews of Biophysics\",\"volume\":\"53 \",\"pages\":\"e2\"},\"PeriodicalIF\":7.2000,\"publicationDate\":\"2020-01-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1017/S003358351900009X\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Quarterly Reviews of Biophysics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1017/S003358351900009X\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOPHYSICS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Quarterly Reviews of Biophysics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1017/S003358351900009X","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOPHYSICS","Score":null,"Total":0}
Spontaneous deamidation prompted backbone isomerization of Asn/Asp residues resulting in - most cases - the insertion of an extra methylene group into the backbone poses a threat to the structural integrity of proteins. Here we present a systematical analysis of how temperature, pH, presence of charged residues, but most importantly backbone conformation and dynamics affect isomerization rates as determined by nuclear magnetic resonance in the case of designed peptide-models. We demonstrate that restricted mobility (such as being part of a secondary structural element) may safeguard against isomerization, but this protective factor is most effective in the case of off-pathway folds which can slow the reaction by several magnitudes compared to their on-pathway counterparts. We show that the geometric descriptors of the initial nucleophilic attack of the isomerization can be used to classify local conformation and contribute to the design of stable protein drugs, antibodies or the assessment of the severity of mutations.
At any –Asn/AspGly– sites in proteins a spontaneous backbone isomerization occurs within days under physiological conditions leading to various forms of proteopathy. This unwanted transformation especially harmful to long-lived proteins (e.g. hemoglobin and crystallins), can be slowed down, though never stopped, by a rigid three-dimensional protein fold, if it can delay in the conformational maze, on-pathway intermediates from occurring.
期刊介绍:
Quarterly Reviews of Biophysics covers the field of experimental and computational biophysics. Experimental biophysics span across different physics-based measurements such as optical microscopy, super-resolution imaging, electron microscopy, X-ray and neutron diffraction, spectroscopy, calorimetry, thermodynamics and their integrated uses. Computational biophysics includes theory, simulations, bioinformatics and system analysis. These biophysical methodologies are used to discover the structure, function and physiology of biological systems in varying complexities from cells, organelles, membranes, protein-nucleic acid complexes, molecular machines to molecules. The majority of reviews published are invited from authors who have made significant contributions to the field, who give critical, readable and sometimes controversial accounts of recent progress and problems in their specialty. The journal has long-standing, worldwide reputation, demonstrated by its high ranking in the ISI Science Citation Index, as a forum for general and specialized communication between biophysicists working in different areas. Thematic issues are occasionally published.