title: Biophysical analysis of anopheles gambiae leucine-rich repeat proteins APL1A1, APL1B [corrected] and APL1C and their interaction with LRIM1.
abstract: Natural infection of Anopheles gambiae by malaria-causing Plasmodium parasites is significantly influenced by the APL1 genetic locus. The locus contains three closely related leucine-rich repeat (LRR) genes, APL1A, APL1B and APL1C. Multiple studies have reported the participation of APL1A-C in the immune response of A. gambiae to invasion by both rodent and human Plasmodium isolates. APL1C forms a heterodimer with the related LRR protein LRIM1 via a C-terminal coiled-coil domain that is also present in APL1A and APL1B. The LRIM1/APL1C heterodimer protects A. gambiae from infection by binding the complement-like protein TEP1 to form a stable and active immune complex. Here we report solution x-ray scatting data for the LRIM1/APL1C heterodimer, the oligomeric state of LRIM1/APL1 LRR domains in solution and the crystal structure of the APL1B LRR domain. The LRIM1/APL1C heterodimeric complex has a flexible and extended structure in solution. In contrast to the APL1A, APL1C and LRIM1 LRR domains, the APL1B LRR domain is a homodimer. The crystal structure of APL1B-LRR shows that the homodimer is formed by an N-terminal helix that complements for the absence of an N-terminal capping motif in APL1B, which is a unique distinction within the LRIM1/APL1 protein family. Full-length APL1A1 and APL1B form a stable complex with LRIM1. These results support a model in which APL1A1, APL1B and APL1C can all form an extended, flexible heterodimer with LRIM1, providing a repertoire of functional innate immune complexes to protect A. gambiae from a diverse array of pathogens.
authors.affiliation: Department of Chemistry and Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Marni
authors.initials: M
authors.lastname: Williams
authors.affiliation: Department of Chemistry and Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Brady J
authors.initials: BJ
authors.lastname: Summers
authors.affiliation: Department of Chemistry and Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Richard H G
authors.initials: RH
authors.lastname: Baxter
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000852:Anopheles / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D019476:Insect Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000090263:Leucine-Rich Repeat Proteins; D008288:Malaria / Q000635:transmission; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010961:Plasmodium / Q000502:physiology; D011487:Protein Conformation; D060066:Protein Interaction Maps; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D019476:Insect Proteins; C540280:LRIM1 protein, Anopheles gambiae; D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins