Structures of C1q-like proteins reveal unique features among the C1q/TNF superfamily.
C1q-like (C1QL) -1, -2, and -3 proteins are encoded by homologous genes that are highly expressed in brain. C1QLs bind to brain-specific angiogenesis inhibitor 3 (BAI3), an adhesion-type G-protein coupled receptor that may regulate dendritic morphology by organizing actin filaments. To begin to understand the function of C1QLs, we determined high-resolution crystal structures of the globular C1q-domains of C1QL1, C1QL2, and C1QL3. Each structure is a trimer, with each protomer forming a jelly-roll fold consisting of 10 β strands. Moreover, C1QL trimers may assemble into higher-order oligomers similar to adiponectin and contain four Ca(2+)-binding sites along the trimeric symmetry axis, as well as additional surface Ca(2+)-binding sites. Mutation of Ca(2+)-coordinating residues along the trimeric symmetry axis lowered the Ca(2+)-binding affinity and protein stability. Our results reveal unique structural features of C1QLs among C1q/TNF superfamily proteins that may be associated with their specific brain functions.
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA. Electronic address: suressl@indiana.edu.
Susanne
S
Ressl
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
Brandon K
BK
Vu
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
Sandro
S
Vivona
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
David C
DC
Martinelli
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
Thomas C
TC
Südhof
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA; Departments of Neurology and Neurological Sciences, Photon Science, and Structural Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: brunger@stanford.edu.
Axel T
AT
Brunger
D052242:Adiponectin / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D015922:Complement C1q / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary
D052242:Adiponectin; D015922:Complement C1q; D002118:Calcium