TY - JOUR
T1 - Existence of different but overlapping IgG- and IgM-binding sites on the globular domain of human C1q
AU - Zlatarova, Alexandra S.
AU - Rouseva, Marieta
AU - Roumenina, Lubka T.
AU - Gadjeva, Mihaela
AU - Kolev, Martin
AU - Dobrev, Ivan
AU - Olova, Neli
AU - Ghai, Rohit
AU - Jensenius, Jens Chr
AU - Reid, Kenneth B.M.
AU - Kishore, Uday
AU - Kojouharova, Mihaela S.
PY - 2006/8/22
Y1 - 2006/8/22
N2 - C1q is the first subcomponent of the classical complement pathway that binds antigen-bound IgG or IgM and initiates complement activation via association of serine proteases C1r and C1s. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the C-terminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has some structural and functional autonomy. Although a number of studies have tried to identify IgG-binding sites on the gC1q domain, no such attempt has been made to localize IgM-binding site. On the basis of the information available via the gC1q crystal structure, molecular modeling, mutational studies, and bioinformatics, we have generated a series of substitution mutants of ghA, ghB, and ghC and examined their interactions with IgM. The comparative analysis of IgM- and IgG-binding abilities of the mutants suggests that the IgG- and IgM-binding sites within the gC1q domain are different but may overlap. Whereas ArgB108, Arg B109, and TyrB175 mainly constitute the IgM-binding site, the residues Arg B114, ArgB129, ArgB163, and HisB117 that have been shown to be central to IgG binding are not important for the C1q-IgM interaction. Given the location of ArgB108, Arg B109, and TyrB175 in the gC1q crystal structure, it is likely that C1q interacts with IgM via the top of the gC1q domain.
AB - C1q is the first subcomponent of the classical complement pathway that binds antigen-bound IgG or IgM and initiates complement activation via association of serine proteases C1r and C1s. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the C-terminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has some structural and functional autonomy. Although a number of studies have tried to identify IgG-binding sites on the gC1q domain, no such attempt has been made to localize IgM-binding site. On the basis of the information available via the gC1q crystal structure, molecular modeling, mutational studies, and bioinformatics, we have generated a series of substitution mutants of ghA, ghB, and ghC and examined their interactions with IgM. The comparative analysis of IgM- and IgG-binding abilities of the mutants suggests that the IgG- and IgM-binding sites within the gC1q domain are different but may overlap. Whereas ArgB108, Arg B109, and TyrB175 mainly constitute the IgM-binding site, the residues Arg B114, ArgB129, ArgB163, and HisB117 that have been shown to be central to IgG binding are not important for the C1q-IgM interaction. Given the location of ArgB108, Arg B109, and TyrB175 in the gC1q crystal structure, it is likely that C1q interacts with IgM via the top of the gC1q domain.
UR - http://www.scopus.com/inward/record.url?scp=33747453509&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33747453509&partnerID=8YFLogxK
U2 - 10.1021/bi060539v
DO - 10.1021/bi060539v
M3 - Article
C2 - 16906756
AN - SCOPUS:33747453509
SN - 0006-2960
VL - 45
SP - 9979
EP - 9988
JO - Biochemistry
JF - Biochemistry
IS - 33
ER -