The closed MTIP-myosin A-tail complex from the malaria parasite invasion machinery.
The Myosin A-tail interacting protein (MTIP) of the malaria parasite links the actomyosin motor of the host cell invasion machinery to its inner membrane complex. We report here that at neutral pH Plasmodium falciparum MTIP in complex with Myosin A adopts a compact conformation, with its two domains completely surrounding the Myosin A-tail helix, dramatically different from previously observed extended MTIP structures. Crystallographic and mutagenesis studies show that H810 and K813 of Myosin A are key players in the formation of the compact MTIP:Myosin A complex. Only the unprotonated state of Myosin A-H810 is compatible with the compact complex. Most surprisingly, every side-chain atom of Myosin A-K813 is engaged in contacts with MTIP. While this side-chain was previously considered to prevent a compact conformation of MTIP with Myosin A, it actually appears to be essential for the formation of the compact complex. The hydrophobic pockets and adaptability seen in the available series of MTIP structures bodes well for the discovery of inhibitors of cell invasion by malaria parasites.
Bosch
Jürgen
J
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Turley
Stewart
S
Roach
Claudia M
CM
Daly
Thomas M
TM
Bergman
Lawrence W
LW
Hol
Wim G J
WG
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D008239:Lysine / Q000737:chemistry; D016778:Malaria, Falciparum / Q000469:parasitology / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D024507:Nonmuscle Myosin Type IIA / Q000737:chemistry* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D020798:Two-Hybrid System Techniques
D002352:Carrier Proteins; D015800:Protozoan Proteins; D024507:Nonmuscle Myosin Type IIA; D008239:Lysine