Formation of two peptide/MHC II isomers is catalyzed differentially by HLA-DM

Michael P Belmares; Robert Busch; Elizabeth D Mellins; Harden M McConnell

doi:10.1021/bi020466p

Formation of two peptide/MHC II isomers is catalyzed differentially by HLA-DM

Michael P Belmares, Robert Busch, Elizabeth D Mellins, Harden M McConnell

Research output: Contribution to journal › Article › peer-review

Abstract

Major histocompatability class II proteins are transmembrane alphabeta-heterodimers that present peptides to T-cells. MHC II may bind exogenous peptides directly at the cell surface. Alternatively, peptides derived from processing of endosomal protein may bind to MHC II in endosomal compartments. There, HLA-DM catalyzes the formation of peptide/MHC complexes, which are then transported to the cell surface. Here we report evidence that the peptide Ii CLIP 81-104 binds to DR*0404 in two alternate registries, whose dissociation rates, while kinetically indistinguishable at pH 5.3 and 37 degrees C, are kinetically resolved in the presence of HLA-DM. In one registry isomer, CLIP Met 91 is placed in the N-terminal P1 pocket of DR*0404, and peptide dissociation is readily catalyzed by HLA-DM. In a second proposed registry, likely with CLIP Leu 97 in the P1 pocket, the complex is substantially less sensitive to HLA-DM catalysis. Without HLA-DM, or at pH 7, the fraction of each isomer formed in solution is relatively insensitive to the duration of incubation with peptide. However, with HLA-DM, the fraction of the DM-insensitive isomer is dramatically influenced by peptide incubation time. The mechanism of isomer formation appears to be determined by the HLA-DM-modified relative association to the two registries, followed by HLA-DM-catalyzed dissociation of each isomer and rebinding, leading to a final isomer composition determined by these kinetic constants. Intramolecular isomer interconversion does not appear to be involved. The behavior of these complexes may provide a model for peptide editing by DM in endosomes.

Original language	English
Pages (from-to)	838-47
Number of pages	10
Journal	Biochemistry
Volume	42
Issue number	3
DOIs	https://doi.org/10.1021/bi020466p
Publication status	Published - 28 Jan 2003

Keywords

Amino Acid Sequence
Animals
Antigens, Differentiation, B-Lymphocyte
Catalysis
Cell Line
Drosophila melanogaster
HLA-D Antigens
HLA-DR4 Antigen
Histocompatibility Antigens Class II
Humans
Isomerism
Kinetics
Molecular Sequence Data
Myelin Basic Protein
Peptide Fragments
Protein Binding
Protein Conformation

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10.1021/bi020466p

Cite this

@article{491b7b438f6142fb81f0c3b93eac6f37,

title = "Formation of two peptide/MHC II isomers is catalyzed differentially by HLA-DM",

abstract = "Major histocompatability class II proteins are transmembrane alphabeta-heterodimers that present peptides to T-cells. MHC II may bind exogenous peptides directly at the cell surface. Alternatively, peptides derived from processing of endosomal protein may bind to MHC II in endosomal compartments. There, HLA-DM catalyzes the formation of peptide/MHC complexes, which are then transported to the cell surface. Here we report evidence that the peptide Ii CLIP 81-104 binds to DR*0404 in two alternate registries, whose dissociation rates, while kinetically indistinguishable at pH 5.3 and 37 degrees C, are kinetically resolved in the presence of HLA-DM. In one registry isomer, CLIP Met 91 is placed in the N-terminal P1 pocket of DR*0404, and peptide dissociation is readily catalyzed by HLA-DM. In a second proposed registry, likely with CLIP Leu 97 in the P1 pocket, the complex is substantially less sensitive to HLA-DM catalysis. Without HLA-DM, or at pH 7, the fraction of each isomer formed in solution is relatively insensitive to the duration of incubation with peptide. However, with HLA-DM, the fraction of the DM-insensitive isomer is dramatically influenced by peptide incubation time. The mechanism of isomer formation appears to be determined by the HLA-DM-modified relative association to the two registries, followed by HLA-DM-catalyzed dissociation of each isomer and rebinding, leading to a final isomer composition determined by these kinetic constants. Intramolecular isomer interconversion does not appear to be involved. The behavior of these complexes may provide a model for peptide editing by DM in endosomes.",

keywords = "Amino Acid Sequence, Animals, Antigens, Differentiation, B-Lymphocyte, Catalysis, Cell Line, Drosophila melanogaster, HLA-D Antigens, HLA-DR4 Antigen, Histocompatibility Antigens Class II, Humans, Isomerism, Kinetics, Molecular Sequence Data, Myelin Basic Protein, Peptide Fragments, Protein Binding, Protein Conformation",

author = "Belmares, {Michael P} and Robert Busch and Mellins, {Elizabeth D} and McConnell, {Harden M}",

year = "2003",

month = jan,

day = "28",

doi = "10.1021/bi020466p",

language = "English",

volume = "42",

pages = "838--47",

journal = "Biochemistry",

issn = "0006-2960",

publisher = "American Chemical Society",

number = "3",

}

TY - JOUR

T1 - Formation of two peptide/MHC II isomers is catalyzed differentially by HLA-DM

AU - Belmares, Michael P

AU - Busch, Robert

AU - Mellins, Elizabeth D

AU - McConnell, Harden M

PY - 2003/1/28

Y1 - 2003/1/28

N2 - Major histocompatability class II proteins are transmembrane alphabeta-heterodimers that present peptides to T-cells. MHC II may bind exogenous peptides directly at the cell surface. Alternatively, peptides derived from processing of endosomal protein may bind to MHC II in endosomal compartments. There, HLA-DM catalyzes the formation of peptide/MHC complexes, which are then transported to the cell surface. Here we report evidence that the peptide Ii CLIP 81-104 binds to DR*0404 in two alternate registries, whose dissociation rates, while kinetically indistinguishable at pH 5.3 and 37 degrees C, are kinetically resolved in the presence of HLA-DM. In one registry isomer, CLIP Met 91 is placed in the N-terminal P1 pocket of DR*0404, and peptide dissociation is readily catalyzed by HLA-DM. In a second proposed registry, likely with CLIP Leu 97 in the P1 pocket, the complex is substantially less sensitive to HLA-DM catalysis. Without HLA-DM, or at pH 7, the fraction of each isomer formed in solution is relatively insensitive to the duration of incubation with peptide. However, with HLA-DM, the fraction of the DM-insensitive isomer is dramatically influenced by peptide incubation time. The mechanism of isomer formation appears to be determined by the HLA-DM-modified relative association to the two registries, followed by HLA-DM-catalyzed dissociation of each isomer and rebinding, leading to a final isomer composition determined by these kinetic constants. Intramolecular isomer interconversion does not appear to be involved. The behavior of these complexes may provide a model for peptide editing by DM in endosomes.

AB - Major histocompatability class II proteins are transmembrane alphabeta-heterodimers that present peptides to T-cells. MHC II may bind exogenous peptides directly at the cell surface. Alternatively, peptides derived from processing of endosomal protein may bind to MHC II in endosomal compartments. There, HLA-DM catalyzes the formation of peptide/MHC complexes, which are then transported to the cell surface. Here we report evidence that the peptide Ii CLIP 81-104 binds to DR*0404 in two alternate registries, whose dissociation rates, while kinetically indistinguishable at pH 5.3 and 37 degrees C, are kinetically resolved in the presence of HLA-DM. In one registry isomer, CLIP Met 91 is placed in the N-terminal P1 pocket of DR*0404, and peptide dissociation is readily catalyzed by HLA-DM. In a second proposed registry, likely with CLIP Leu 97 in the P1 pocket, the complex is substantially less sensitive to HLA-DM catalysis. Without HLA-DM, or at pH 7, the fraction of each isomer formed in solution is relatively insensitive to the duration of incubation with peptide. However, with HLA-DM, the fraction of the DM-insensitive isomer is dramatically influenced by peptide incubation time. The mechanism of isomer formation appears to be determined by the HLA-DM-modified relative association to the two registries, followed by HLA-DM-catalyzed dissociation of each isomer and rebinding, leading to a final isomer composition determined by these kinetic constants. Intramolecular isomer interconversion does not appear to be involved. The behavior of these complexes may provide a model for peptide editing by DM in endosomes.

KW - Amino Acid Sequence

KW - Animals

KW - Antigens, Differentiation, B-Lymphocyte

KW - Catalysis

KW - Cell Line

KW - Drosophila melanogaster

KW - HLA-D Antigens

KW - HLA-DR4 Antigen

KW - Histocompatibility Antigens Class II

KW - Humans

KW - Isomerism

KW - Kinetics

KW - Molecular Sequence Data

KW - Myelin Basic Protein

KW - Peptide Fragments

KW - Protein Binding

KW - Protein Conformation

U2 - 10.1021/bi020466p

DO - 10.1021/bi020466p

M3 - Article

C2 - 12534297

SN - 0006-2960

VL - 42

SP - 838

EP - 847

JO - Biochemistry

JF - Biochemistry

IS - 3

ER -