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Structural and biochemical analysis of highly similar HLA-B allotypes differentially associated with type 1 diabetes.

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Title: Structural and biochemical analysis of highly similar HLA-B allotypes differentially associated with type 1 diabetes.
Authors: Sharma, Ruby1, Amdare, Nitin P.1, Ghosh, Agnidipta2, Schloss, Jennifer1, Sidney, John3, Garforth, Scott J.2, Lopez, Yessenia1, Celikgil, Alev2, Sette, Alessandro3,4, Almo, Steven C.2 steve.almo@einsteinmed.edu, DiLorenzo, Teresa P.1,5,6,7 teresa.dilorenzo@einsteinmed.edu
Source: Journal of Biological Chemistry. Sep2024, Vol. 300 Issue 9, p1-14. 14p.
Subjects: HLA histocompatibility antigens, Pancreatic beta cells, Type 1 diabetes, Peptides, Islands of Langerhans, T cell receptors
Abstract: Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. CD8+ T cells, responding to beta cell peptides presented by class I major histocompatibility complex (MHC) molecules, are important effectors leading to beta cell elimination. Human leukocyte antigen (HLA) B∗39:06, B∗39:01, and B∗38:01 are closely related class I MHC allotypes that nonetheless show differential association with T1D. HLA-B∗39:06 is the most predisposing of all HLA class I molecules and is associated with early age at disease onset. B∗39:01 is also associated with susceptibility to T1D, but to a lesser extent, though differing from B∗39:06 by only two amino acids. HLA-B∗38:01, in contrast, is associated with protection from the disease. Upon identifying a peptide that binds to both HLA-B∗39:06 and B∗39:01, we determined the respective X-ray structures of the two allotypes presenting this peptide to 1.7 Å resolution. The peptide residues available for T cell receptor contact and those serving as anchors were identified. Analysis of the F pocket of HLA-B∗39:06 and B∗39:01 provided an explanation for the distinct peptide C terminus preferences of the two allotypes. Structure-based modeling of the protective HLA-B∗38:01 suggested a potential reason for its peptide preferences and its reduced propensity to present 8-mer peptides compared to B∗39:06. Notably, the three allotypes showed differential binding to peptides derived from beta cell autoantigens. Taken together, our findings should facilitate identification of disease-relevant candidate T cell epitopes and structure-guided therapeutics to interfere with peptide binding. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
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PubType: Academic Journal
PubTypeId: academicJournal
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  Data: Structural and biochemical analysis of highly similar HLA-B allotypes differentially associated with type 1 diabetes.
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  Data: <searchLink fieldCode="AR" term="%22Sharma%2C+Ruby%22">Sharma, Ruby</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Amdare%2C+Nitin+P%2E%22">Amdare, Nitin P.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Ghosh%2C+Agnidipta%22">Ghosh, Agnidipta</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Schloss%2C+Jennifer%22">Schloss, Jennifer</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Sidney%2C+John%22">Sidney, John</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Garforth%2C+Scott+J%2E%22">Garforth, Scott J.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Lopez%2C+Yessenia%22">Lopez, Yessenia</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Celikgil%2C+Alev%22">Celikgil, Alev</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Sette%2C+Alessandro%22">Sette, Alessandro</searchLink><relatesTo>3,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Almo%2C+Steven+C%2E%22">Almo, Steven C.</searchLink><relatesTo>2</relatesTo><i> steve.almo@einsteinmed.edu</i><br /><searchLink fieldCode="AR" term="%22DiLorenzo%2C+Teresa+P%2E%22">DiLorenzo, Teresa P.</searchLink><relatesTo>1,5,6,7</relatesTo><i> teresa.dilorenzo@einsteinmed.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. Sep2024, Vol. 300 Issue 9, p1-14. 14p.
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  Data: <searchLink fieldCode="DE" term="%22HLA+histocompatibility+antigens%22">HLA histocompatibility antigens</searchLink><br /><searchLink fieldCode="DE" term="%22Pancreatic+beta+cells%22">Pancreatic beta cells</searchLink><br /><searchLink fieldCode="DE" term="%22Type+1+diabetes%22">Type 1 diabetes</searchLink><br /><searchLink fieldCode="DE" term="%22Peptides%22">Peptides</searchLink><br /><searchLink fieldCode="DE" term="%22Islands+of+Langerhans%22">Islands of Langerhans</searchLink><br /><searchLink fieldCode="DE" term="%22T+cell+receptors%22">T cell receptors</searchLink>
– Name: Abstract
  Label: Abstract
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  Data: Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of the insulin-producing beta cells in the pancreatic islets of Langerhans. CD8+ T cells, responding to beta cell peptides presented by class I major histocompatibility complex (MHC) molecules, are important effectors leading to beta cell elimination. Human leukocyte antigen (HLA) B∗39:06, B∗39:01, and B∗38:01 are closely related class I MHC allotypes that nonetheless show differential association with T1D. HLA-B∗39:06 is the most predisposing of all HLA class I molecules and is associated with early age at disease onset. B∗39:01 is also associated with susceptibility to T1D, but to a lesser extent, though differing from B∗39:06 by only two amino acids. HLA-B∗38:01, in contrast, is associated with protection from the disease. Upon identifying a peptide that binds to both HLA-B∗39:06 and B∗39:01, we determined the respective X-ray structures of the two allotypes presenting this peptide to 1.7 Å resolution. The peptide residues available for T cell receptor contact and those serving as anchors were identified. Analysis of the F pocket of HLA-B∗39:06 and B∗39:01 provided an explanation for the distinct peptide C terminus preferences of the two allotypes. Structure-based modeling of the protective HLA-B∗38:01 suggested a potential reason for its peptide preferences and its reduced propensity to present 8-mer peptides compared to B∗39:06. Notably, the three allotypes showed differential binding to peptides derived from beta cell autoantigens. Taken together, our findings should facilitate identification of disease-relevant candidate T cell epitopes and structure-guided therapeutics to interfere with peptide binding. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1016/j.jbc.2024.107702
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 14
        StartPage: 1
    Subjects:
      – SubjectFull: HLA histocompatibility antigens
        Type: general
      – SubjectFull: Pancreatic beta cells
        Type: general
      – SubjectFull: Type 1 diabetes
        Type: general
      – SubjectFull: Peptides
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      – SubjectFull: Islands of Langerhans
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      – SubjectFull: T cell receptors
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      – TitleFull: Structural and biochemical analysis of highly similar HLA-B allotypes differentially associated with type 1 diabetes.
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              Text: Sep2024
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              Y: 2024
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