CoChat
Sign Up
Cited by 196Protein Structure and DynamicsMonoclonal and Polyclonal Antibodies ResearchT-cell and B-cell Immunology

How antibodies fold

Open access
Feige, Matthias J., Hendershot, Linda M., Buchner, Johannes·2010·Trends in Biochemical Sciences
DOI 10.1016/j.tibs.2009.11.005PMC PMC4716677
Open this paper in CoChat — free account

Abstract

B cells use unconventional strategies for the production of a seemingly unlimited number of antibodies from a very limited amount of DNA. These methods dramatically increase the likelihood of producing proteins that cannot fold or assemble appropriately. B cells are therefore particularly dependent on 'quality control' mechanisms to oversee antibody production. Recent in vitro experiments demonstrate that Ig domains have evolved diverse folding strategies ranging from robust spontaneous folding to intrinsically disordered domains that require assembly with their partner domains to fold; in vivo experiments reveal that these different folding characteristics form the basis for cellular checkpoints in Ig transport. Taken together, these reports provide a detailed understanding of how B cells monitor and ensure the functional fidelity of Ig proteins.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.tibs.2009.11.005

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Correct folding of scFv and Fab fragments is highly dependent on the activity of PPIases.

    “In particular, the correct folding of scFv and Fab fragments has been found to be highly dependent on the activity of PPIases [162].”

    From Evolution of Escherichia coli Expression System in Producing Antibody Recombinant Fragments (2020) · cites this paper as [162]

    The section ‘From the folding of antibody domains to complete IgG molecules’ (page unavailable) says that proline isomerization is rate-limiting for CH1 folding and relates this step to Fab folding. The concluding remarks also say that peptidyl-prolyl isomerization controls antibody folding. Neither passage establishes that correct folding of both scFv and Fab fragments is highly dependent on PPIase enzyme activity; a requirement for isomerization is not itself evidence of dependence on those enzymes. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 102

  1. [2]Maki R Exon shuffling generates an immunoglobulin heavy chain gene Proc. Natl. Acad. Sci. U. S. A 1980 77 2138 2142 6769120 PMC348667
  2. [3]Early P An immunoglobulin heavy chain variable region gene is generated from three segments of DNA: VH D and JH Cell 1980 19 981 992 6769593
  3. [4]Calame K Mouse Cmu heavy chain immunoglobulin gene segment contains three intervening sequences separating domains Nature 1980 284 452 455 6767197
  4. [5]Alt FW Development of the primary antibody repertoire Science 1987 238 1079 1087 3317825
  5. [6]Bernard O Sequences of mouse immunoglobulin light chain genes before and after somatic changes Cell 1978 15 1133 1144 103630
  6. [7]Bergman LW Kuehl WM Formation of an intrachain disulfide bond on nascent immunoglobulin light chains J. Biol. Chem 1979 254 8869 8876 113402
  7. [8]Baumal R Synthesis, assembly, and secretion of gamma globulin by mouse myeloma cells. 3. Assembly of the three subclasses of IgG J. Exp. Med 1971 134 1316 1334 5112205 PMC2139014
  8. [9]Zack DJ Somatically generated mouse myeloma variants synthesizing IgA half-molecules J. Exp. Med 1981 154 1554 1569 7299348 PMC2186520
  9. [10]Bergman LW Kuehl WM Temporal relationship of translation and glycosylation of immunoglobulin heavy and light chains Biochemistry 1978 17 5174 5180 103571
  10. [11]Huber R Crystallographic structure studies of an IgG molecule and an Fc fragment Nature 1976 264 415 420 1004567
  11. [12]Krapp S Structural analysis of human IgG-Fc glycoforms reveals a correlation between glycosylation and structural integrity Journal of Molecular Biology 2003 325 979 989 12527303
  12. [13]Feige MJ Structure of the murine unglycosylated IgG1 Fc fragment J. Mol. Biol 2009 391 599 608 19559712
  13. [14]Sitia R The role of glycosylation in secretion and membrane expression of immunoglobulins M and A Mol. Immunol 1984 21 709 719 6749140
  14. [15]Hickman S Kornfeld S Effect of tunicamycin on IgM, IgA, and IgG secretion by mouse plasmacytoma cells J. Immunol 1978 121 990 996 690446
  15. [16]Kalmanson GM Bronfenbrenner J The reversal of Pneumococcus Quellung by digestion of the antibody with papain Science 1942 96 21 22 17838647
  16. [17]Porter RR The formation of a specific inhibitor by hydrolysis of rabbit antiovalbumin Biochem. J 1950 46 479 484 15420176 PMC1275451
  17. [18]Bork P The Immunoglobulin Fold - Structural Classification, Sequence Patterns and Common Core Journal of Molecular Biology 1994 242 309 320 7932691
  18. [19]Goto Y Hamaguchi K Role of the Intrachain Disulfide Bond in the Conformation and Stability of the Constant Fragment of the Immunoglobulin Light Chain Journal of Biochemistry 1979 86 1433 1441 118170
  19. [20]Du PL Immunoglobulin superfamily receptors in protochordates: before RAG time Immunol. Rev 2004 198 233 248 15199966
  20. [21]Hsu E The plasticity of immunoglobulin gene systems in evolution Immunol. Rev 2006 210 8 26 16623761 PMC2569000
  21. [22]Dooley H Flajnik MF Antibody repertoire development in cartilaginous fish Dev. Comp Immunol 2006 30 43 56 16146649
  22. [23]Williams AF Barclay AN The immunoglobulin superfamily--domains for cell surface recognition Annu. Rev. Immunol 1988 6 381 405 3289571
  23. [24]Barclay AN Membrane proteins with immunoglobulin-like domains--a master superfamily of interaction molecules Semin. Immunol 2003 15 215 223 14690046
  24. [25]Rougon G Hobert O New insights into the diversity and function of neuronal immunoglobulin superfamily molecules Annu. Rev. Neurosci 2003 26 207 238 12598678
  25. [26]Halaby DM Mornon JP The immunoglobulin superfamily: an insight on its tissular, species, and functional diversity J. Mol. Evol 1998 46 389 400 9541533
  26. [27]Goto Y Hamaguchi K Unfolding and Refolding of the Constant Fragment of the Immunoglobulin Light Chain Journal of Molecular Biology 1982 156 891 910 6811753
  27. [28]Goto Y Hamaguchi K Unfolding and Refolding of the Reduced Constant Fragment of the Immunoglobulin Light Chain - Kinetic Role of the Intrachain Disulfide Bond Journal of Molecular Biology 1982 156 911 926 6811754
  28. [29]Isenman D Folding Pathways of Immunoglobulin Domains. The Folding Kinetics of the C3 Domain of Human IgG Biochemsitry 1979 18 3327 3336 465472
  29. [30]Ramm K Removal of the conserved disulfide bridges from the scFv fragment of an antibody: effects on folding kinetics and aggregation J. Mol. Biol 1999 290 535 546 10390351
  30. [31]Feige MJ Folding mechanism of the C(H)2 antibody domain Journal of Molecular Biology 2004 344 107 118 15504405
  31. [32]Lilie H Association of antibody chains at different stages of folding: prolyl isomerization occurs after formation of quaternary structure J. Mol. Biol 1995 248 190 201 7731044
  32. [33]Thies MJW Folding and association of the antibody domain C(H)3: Prolyl isomerization preceeds dimerization Journal of Molecular Biology 1999 293 67 79 10512716
  33. [34]Feige MJ The structure of a folding intermediate provides insight into differences in immunoglobulin amyloidogenicity Proc. Natl. Acad. Sci. U. S. A 2008 105 13373 13378 18768806 PMC2533197
  34. [35]Freund C Folding nuclei of the scFv fragment of an antibody Biochemistry 1996 35 8457 8464 8679604
  35. [36]Feige MJ Influence of the internal disulfide bridge on the folding pathway of the C-L antibody domain Journal of Molecular Biology 2007 365 1232 1244 17112539
  36. [37]Feige MJ An unfolded CH1 domain controls the assembly and secretion of IgG antibodies Mol. Cell 2009 34 569 579 19524537 PMC2908990
  37. [38]Simpson ER The Folding Pathway of the Antibody V(L) Domain J. Mol. Biol 2009 19647749
  38. [39]Thies MJ Folding and oxidation of the antibody domain C(H)3 J. Mol. Biol 2002 319 1267 1277 12079363
  39. [40]Geierhaas CD Comparison of the transition states for folding of two Ig-like proteins from different superfamilies J. Mol. Biol 2004 343 1111 1123 15476825
  40. [41]Lappalainen I Plasticity within the obligatory folding nucleus of an immunoglobulin-like domain J. Mol. Biol 2008 375 547 559 18022190 PMC2291451
  41. [42]Mizuguchi M Folding of a beta-sheet protein monitored by real-time NMR spectroscopy Journal of Molecular Biology 2003 328 1161 1171 12729749
  42. [43]Kameda A Nuclear magnetic resonance characterization of the refolding intermediate of beta(2)-microglobulin trapped by non-native prolyl peptide bond Journal of Molecular Biology 2005 348 383 397 15811375
  43. [44]Jahn TR Amyloid formation under physiological conditions proceeds via a native-like folding intermediate Nature Structural & Molecular Biology 2006 13 195 201 16491092
  44. [45]Qin ZJ Structural characterization of the partially folded intermediates of an immunoglobulin light chain leading to amyloid fibrillation and amorphous aggregation Biochemistry 2007 46 3521 3531 17315948
  45. [46]Kudo A Melchers F A second gene, VpreB in the lambda 5 locus of the mouse, which appears to be selectively expressed in pre-B lymphocytes EMBO J 1987 6 2267 2272 3117530 PMC553628
  46. [47]Sakaguchi N Melchers F Lambda 5, a new light-chain-related locus selectively expressed in pre-B lymphocytes Nature 1986 324 579 582 3024017
  47. [48]Karasuyama H The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain J. Exp. Med 1990 172 969 972 2117638 PMC2188555
  48. [49]Shaffer AL Schlissel MS A truncated heavy chain protein relieves the requirement for surrogate light chains in early B cell development J. Immunol 1997 159 1265 1275 9233622
  49. [50]Mains PE Sibley CH The requirement of light chain for the surface deposition of the heavy chain of immunoglobulin M J. Biol. Chem 1983 258 5027 5033 6403541
  50. [51]Coffino P Scharff MD Rate of somatic mutation in immunoglobulin production by mouse myeloma cells Proc. Natl. Acad. Sci. U. S. A 1971 68 219 223 5276293 PMC391199
  51. [52]Kohler G Immunoglobulin chain loss in hybridoma lines Proc. Natl. Acad. Sci. U. S. A 1980 77 2197 2199 6769123 PMC348679
  52. [53]Seligmann M Heavy chain diseases: current findings and concepts Immunol. Rev 1979 48 145 167 121099
  53. [54]Morrison SL Murine heavy chain disease Eur. J. Immunol 1978 8 194 199 95958
  54. [55]Hamers-Casterman C Naturally-Occurring Antibodies Devoid of Light-Chains Nature 1993 363 446 448 8502296
  55. [56]Lippincott-Schwartz J Degradation from the endoplasmic reticulum: disposing of newly synthesized proteins Cell 1988 54 209 220 3292055
  56. [57]Vembar SS Brodsky JL One step at a time: endoplasmic reticulum-associated degradation Nat. Rev. Mol. Cell Biol 2008 9 944 957 19002207 PMC2654601
  57. [58]Haas IG Wabl M Immunoglobulin heavy chain binding protein Nature 1983 306 387 389 6417546
  58. [59]Bole DG Posttranslational Association of Immunoglobulin Heavy-Chain Binding-Protein with Nascent Heavy-Chains in Nonsecreting and Secreting Hybridomas Journal of Cell Biology 1986 102 1558 1566 3084497 PMC2114236
  59. [60]Haas IG Meo T cDNA cloning of the immunoglobulin heavy chain binding protein Proc. Natl. Acad. Sci. U. S. A 1988 85 2250 2254 2895472 PMC279968
  60. [61]Munro S Pelham HR A C-terminal signal prevents secretion of luminal ER proteins Cell 1987 48 899 907 3545499
  61. [62]Hellman R The in vivo association of BiP with newly synthesized proteins is dependent on the rate and stability of folding and not simply on the presence of sequences that can bind to BiP J. Cell Biol 1999 144 21 30 9885241 PMC2148116
  62. [63]Lee YK BiP and immunoglobulin light chain cooperate to control the folding of heavy chain and ensure the fidelity of immunoglobulin assembly Molecular Biology of the Cell 1999 10 2209 2219 10397760 PMC25436
  63. [64]Knarr G BiP binding sequences in antibodies J. Biol. Chem 1995 270 27589 27594 7499221
  64. [66]Braakman I Manipulating disulfide bond formation and protein folding in the endoplasmic reticulum EMBO J 1992 11 1717 1722 1582407 PMC556629
  65. [67]Vanhove M Unassembled Ig heavy chains do not cycle from BiP in vivo but require light chains to trigger their release Immunity 2001 15 105 114 11485742
  66. [69]Dul JL Ig light chains are secreted predominantly as monomers J. Immunol 1996 157 2969 2975 8816404
  67. [70]Leitzgen K Assembly of immunoglobulin light chains as a prerequisite for secretion. A model for oligomerization-dependent subunit folding J. Biol. Chem 1997 272 3117 3123 9006964
  68. [71]Horibata K Harris AW Mouse myelomas and lymphomas in culture Exp. Cell Res 1970 60 61 77 5439579
  69. [72]Skowronek MH The variable domain of nonassembled Ig light chains determines both their half-life and binding to the chaperone BiP Proc. Natl. Acad. Sci. U. S. A 1998 95 1574 1578 9465057 PMC19100
  70. [73]Wiens GD Harmful somatic mutations: lessons from the dark side Immunol. Rev 1998 162 197 209 9602365
  71. [74]Komar AA A pause for thought along the co-translational folding pathway Trends Biochem. Sci 2009 34 16 24 18996013
  72. [75]Reimer U Side-chain effects on peptidyl-prolyl cis/trans isomerisation J. Mol. Biol 1998 279 449 460 9642049
  73. [76]Stewart DE Occurrence and role of cis peptide bonds in protein structures J. Mol. Biol 1990 214 253 260 2370664
  74. [77]Brandts JF Consideration of the Possibility that the slow step in protein denaturation reactions is due to cis-trans isomerism of proline residues Biochemistry 1975 14 4953 4963 241393
  75. [78]Schmid FX Baldwin RL Acid catalysis of the formation of the slow-folding species of RNase A: evidence that the reaction is proline isomerization Proc. Natl. Acad. Sci. U. S. A 1978 75 4764 4768 283390 PMC336200
  76. [79]Eckert B Prolyl isomerization as a molecular timer in phage infection Nat. Struct. Mol. Biol 2005 12 619 623 15937494
  77. [80]Lu KP Prolyl cis-trans isomerization as a molecular timer Nat. Chem. Biol 2007 3 619 629 17876319
  78. [81]Fischer G Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins Nature 1989 337 476 478 2492638
  79. [82]Lang K Catalysis of protein folding by prolyl isomerase Nature 1987 329 268 270 3306408
  80. [83]Buchner J Alternatively folded states of an immunoglobulin Biochemistry 1991 30 6922 6929 1906346
  81. [84]Thies MJ The alternatively folded state of the antibody C(H)3 domain J. Mol. Biol 2001 309 1077 1085 11399080
  82. [85]Bellotti V Review: Immunoglobulin light chain amyloidosis - The archetype of structural and pathogenic variability Journal of Structural Biology 2000 130 280 289 10940232
  83. [86]Anelli T Thiol-mediated protein retention in the endoplasmic reticulum: the role of ERp44 EMBO J 2003 22 5015 5022 14517240 PMC204474
  84. [87]Melnick J Sequential interaction of the chaperones BiP and GRP94 with immunoglobulin chains in the endoplasmic reticulum Nature 1994 370 373 375 7913987
  85. [88]Hochstenbach F Endoplasmic reticulum resident protein of 90 kilodaltons associates with the T- and B-cell antigen receptors and major histocompatibility complex antigens during their assembly Proc. Natl. Acad. Sci. U. S. A 1992 89 4734 4738 1584811 PMC49158
  86. [89]Brightman SE Isolation of a mouse cDNA encoding MTJ1, a new murine member of the DnaJ family of proteins Gene 1995 153 249 254 7875597
  87. [90]Tyedmers J Homologs of the yeast Sec complex subunits Sec62p and Sec63p are abundant proteins in dog pancreas microsomes Proc. Natl. Acad. Sci. U. S. A 2000 97 7214 7219 10860986 PMC16525
  88. [91]Meunier L A sub-set of chaperones and folding enzymes form multi-protein complexes in the ER to bind nascent proteins Molecular Biology of the Cell 2002 12 488A PMC138646 12475965
  89. [92]Shen Y Identification and characterization of a novel endoplasmic reticulum (ER) DnaJ homologue, which stimulates ATPase activity of BiP in vitro and is induced by ER stress J. Biol. Chem 2002 277 15947 15956 11836248
  90. [93]Cunnea PM ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress J. Biol. Chem 2003 278 1059 1066 12411443
  91. [94]Rutkowski DT The role of p58IPK in protecting the stressed endoplasmic reticulum Mol. Biol. Cell 2007 18 3681 3691 17567950 PMC1951758
  92. [95]Zahedi RP Analysis of the membrane proteome of canine pancreatic rough microsomes identifies a novel Hsp40, termed ERj7 Proteomics 2009 9 3463 3473 19579229
  93. [96]Chen X The 170 kDa glucose regulated stress protein is a large HSP70-, HSP110-like protein of the endoplasmic reticulum FEBS Lett 1996 380 68 72 8603749
  94. [97]Chung KT BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP J. Biol. Chem 2002 277 47557 47563 12356756
  95. [98]Hayashi T Su TP Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival Cell 2007 131 596 610 17981125
  96. [99]Roth RA Pierce SB In vivo cross-linking of protein disulfide isomerase to immunoglobulins Biochemistry 1987 26 4179 4182 3663584
  97. [100]van Anken E Efficient IgM assembly and secretion require the plasma cell induced endoplasmic reticulum protein pERp1 Proc. Natl. Acad. Sci. U. S. A 2009 PMC2761347 19805154
  98. [101]Shimizu Y pERp1 is significantly up-regulated during plasma cell differentiation and contributes to the oxidative folding of immunoglobulin Proc. Natl. Acad. Sci. U. S. A 2009 PMC2761359 19805157
  99. [102]Rupp K Effects of CaBP2, the rat analog of ERp72, and of CaBP1 on the refolding of denatured reduced proteins. Comparison with protein disulfide isomerase J. Biol. Chem 1994 269 2501 2507 8300576
  100. [103]Lindquist JA ER-60, a chaperone with thiol-dependent reductase activity involved in MHC class I assembly EMBO J 1998 17 2186 2195 9545232 PMC1170563
  101. [104]Mkrtchian S A stress-inducible rat liver endoplasmic reticulum protein, ERp29 Eur. J. Biochem 1998 251 304 313 9492298
  102. [105]Rao AK Biosynthesis of the carbohydrate units of immunoglobulins. 1. Purification and properties of galactosyltransferases from swine mesentary lymph nodes Biochemistry 1976 15 5001 5009 990260

Cited by

Sorted by citations

Authors
Feige, M. J., Hendershot, L. M., & Buchner, J.
Affiliations
  • Center for Integrated Protein Science Munich (DE)
  • St. Jude Children's Research Hospital (US)
Corresponding author
Hendershot, Linda M.
ORCID
Venue
Trends in Biochemical Sciences
Publisher
Elsevier BV
Published
2010-04
Volume
35
Issue
4
Pages
189-198
ISSN
0968-0004 (ISSN-L)
DOI
10.1016/j.tibs.2009.11.005
PMC
PMC4716677
OpenAlex
W2012968301
Cited by
196
References
1
Citations by year
2026: 9 · 2025: 9 · 2024: 11 · 2023: 17 · 2022: 17 · 2021: 20 · 2020: 14 · 2019: 17 · 2018: 11 · 2017: 11 · 2016: 7 · 2015: 8 · 2014: 10 · 2013: 12 · 2012: 12
FWCI
0.59
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Biochemical Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (CA21765, P30CA021765)
  • National Institute of General Medical Sciences (GM 54068, R01GM054068)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
antibody folding, immunoglobulin domains, B cells, antibody quality control, intrinsically disordered regions, antibody diversity
MeSH terms
Antibodies, Antigens, Surface, B-Lymphocytes, Immunoglobulin Variable Region, Protein Folding, Immunoglobulin Subunits

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review