免疫球蛋白VL结构域互补决定区中的不稳定环交换。
Destabilizing loop swaps in the CDRs of an immunoglobulin VL domain.
作者信息
Helms L R, Wetzel R
机构信息
Macromolecular Sciences Department, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
出版信息
Protein Sci. 1995 Oct;4(10):2073-81. doi: 10.1002/pro.5560041012.
Abstract
It is generally believed that loop regions in globular proteins, and particularly hypervariable loops in immunoglobulins, can accommodate a wide variety of sequence changes without jeopardizing protein structure or stability. We show here, however, that novel sequences introduced within complementarity determining regions (CDRs) 1 and 3 of the immunoglobulin variable domain REI VL can significantly diminish the stability of the native state of this protein. Besides their implications for the general role of loops in the stability of globular proteins, these results suggest previously unrecognized stability constraints on the variability of CDRs that may impact efforts to engineer new and improved activities into antibodies.
摘要
一般认为，球状蛋白质中的环区，尤其是免疫球蛋白中的高变环，能够容纳各种各样的序列变化而不危及蛋白质结构或稳定性。然而，我们在此表明，引入免疫球蛋白可变结构域REI VL的互补决定区（CDR）1和3内的新序列可显著降低该蛋白质天然状态的稳定性。除了对环区在球状蛋白质稳定性中的一般作用有影响外，这些结果还表明了对CDR变异性以前未被认识到的稳定性限制，这可能会影响将新的和改进的活性引入抗体的工程化努力。
相似文献
1
Destabilizing loop swaps in the CDRs of an immunoglobulin VL domain.
Protein Sci. 1995 Oct;4(10):2073-81. doi: 10.1002/pro.5560041012.
2
Heat-induced native dimerization prevents amyloid formation by variable domain from immunoglobulin light-chain REI.
FEBS J. 2017 Sep;284(18):3114-3127. doi: 10.1111/febs.14181. Epub 2017 Aug 13.
3
Decreased amyloidogenicity caused by mutational modulation of surface properties of the immunoglobulin light chain BRE variable domain.
Biochemistry. 2014 Aug 12;53(31):5162-73. doi: 10.1021/bi5007892. Epub 2014 Aug 4.
4
Contributions of a highly conserved VH/VL hydrogen bonding interaction to scFv folding stability and refolding efficiency.
Biophys J. 1998 Sep;75(3):1473-82. doi: 10.1016/S0006-3495(98)74066-4.
5
Folding of an antibody variable domain in two functional conformations in vitro: calorimetric and spectroscopic study of the anti-ferritin antibody VL domain.
Protein Eng Des Sel. 2007 Oct;20(10):481-90. doi: 10.1093/protein/gzm034. Epub 2007 Oct 24.
6
Rearrangement of the former VL interface in the solution structure of a camelised, single antibody VH domain.
J Mol Biol. 1996 Jun 28;259(5):957-69. doi: 10.1006/jmbi.1996.0373.
7
Increasing protein stability by polar surface residues: domain-wide consequences of interactions within a loop.
Biophys J. 2002 Jan;82(1 Pt 1):391-8. doi: 10.1016/S0006-3495(02)75403-9.
8
Conformational flexibility of a human immunoglobulin light chain variable domain by relaxation dispersion nuclear magnetic resonance spectroscopy: implications for protein misfolding and amyloid assembly.
Biochemistry. 2011 Jul 5;50(26):5845-57. doi: 10.1021/bi200410c. Epub 2011 Jun 9.
9
The Antibody Light-Chain Linker Is Important for Domain Stability and Amyloid Formation.
J Mol Biol. 2015 Nov 6;427(22):3572-3586. doi: 10.1016/j.jmb.2015.09.012. Epub 2015 Sep 25.
10
Characterization of the backbone dynamics of an anti-digoxin antibody VL domain by inverse detected 1H-15N NMR: comparisons with X-ray data for the Fab.
Proteins. 1993 Mar;15(3):290-311. doi: 10.1002/prot.340150307.
引用本文的文献
1
Molecular mechanism of amyloidogenic mutations in hypervariable regions of antibody light chains.
J Biol Chem. 2021 Jan-Jun;296:100334. doi: 10.1016/j.jbc.2021.100334. Epub 2021 Jan 26.
2
Effect of Single Amino Acid Substitutions by Asn and Gln on Aggregation Properties of Bence-Jones Protein BIF.
Int J Mol Sci. 2019 Oct 20;20(20):5197. doi: 10.3390/ijms20205197.
3
Advances in Antibody Design.
Annu Rev Biomed Eng. 2015;17:191-216. doi: 10.1146/annurev-bioeng-071114-040733. Epub 2015 Aug 14.
4
Interrogating and predicting tolerated sequence diversity in protein folds: application to E. elaterium trypsin inhibitor-II cystine-knot miniprotein.
PLoS Comput Biol. 2009 Sep;5(9):e1000499. doi: 10.1371/journal.pcbi.1000499. Epub 2009 Sep 4.
5
Analysis of somatic hypermutation and antigenic selection in the clonal B cell in immunoglobulin light chain amyloidosis (AL).
J Clin Immunol. 2004 Jul;24(4):340-53. doi: 10.1023/B:JOCI.0000029113.68758.9f.
6
Structural relationship of kappa-type light chains with AL amyloidosis: multiple deletions found in a VkappaIV protein.
Clin Exp Immunol. 1999 Dec;118(3):344-8. doi: 10.1046/j.1365-2249.1999.00939.x.
7
Physicochemical consequences of amino acid variations that contribute to fibril formation by immunoglobulin light chains.
Protein Sci. 1999 Mar;8(3):509-17. doi: 10.1110/ps.8.3.509.
8
Mutagenesis of histidine 26 demonstrates the importance of loop-loop and loop-protein interactions for the function of iso-1-cytochrome c.
Protein Sci. 1998 Apr;7(4):994-1005. doi: 10.1002/pro.5560070417.
本文引用的文献
1
Temperature-sensitive mutations and second-site suppressor substitutions affect folding of the P22 tailspike protein in vitro.
J Biol Chem. 1993 Sep 25;268(27):20071-5.
2
Structural and genetic analysis of protein stability.
Annu Rev Biochem. 1993;62:139-60. doi: 10.1146/annurev.bi.62.070193.001035.
3
Strong inhibition of fibrinogen binding to platelet receptor alpha IIb beta 3 by RGD sequences installed into a presentation scaffold.
Protein Eng. 1993 Sep;6(7):745-54. doi: 10.1093/protein/6.7.745.
4
Context dependence of protein secondary structure formation: the three-dimensional structure and stability of a hybrid between chymotrypsin inhibitor 2 and helix E from subtilisin Carlsberg.
Biochemistry. 1993 Oct 19;32(41):11007-14. doi: 10.1021/bi00092a009.
5
A role for destabilizing amino acid replacements in light-chain amyloidosis.
Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5446-50. doi: 10.1073/pnas.91.12.5446.
6
Crystal structure of the tenth type III cell adhesion module of human fibronectin.
J Mol Biol. 1994 Mar 4;236(4):1079-92. doi: 10.1016/0022-2836(94)90013-2.
7
A soluble immunoglobulin variable domain without a disulfide bridge: construction, accumulation in the cytoplasm of E. coli, purification and physicochemical characterization.
Biol Chem Hoppe Seyler. 1994 May;375(5):353-6.
8
Proteolytic excision and in situ cyclization of a bioactive loop from an REI-VL presentation scaffold.
Protein Sci. 1994 Jul;3(7):1108-13. doi: 10.1002/pro.5560030714.
9
Engineered turns of a recombinant antibody improve its in vivo folding.
Protein Eng. 1995 Jan;8(1):81-9. doi: 10.1093/protein/8.1.81.
10
Engineering surface loops of proteins--a preferred strategy for obtaining new enzyme function.
Trends Biotechnol. 1994 May;12(5):207-11. doi: 10.1016/0167-7799(94)90084-1.
Zotero 插件