scholarly journals Structure of an atypical homodimeric actin capping protein from the malaria parasite

2020 ◽  
Author(s):  
Ábris Ádám Bendes ◽  
Petri Kursula ◽  
Inari Kursula
Keyword(s):  
Crystal Structure ◽  
Actin Filament ◽  
Plasmodium Berghei ◽  
Malaria Parasite ◽  
Gliding Motility ◽  
Actin Dynamics ◽  
Structural Elements ◽  
Β Subunit ◽  
Capping Proteins ◽  
Actin Capping

AbstractActin capping proteins (CPs) are essential regulators of actin dynamics in all eukaryotes. Their structure and function have been extensively characterized in higher eukaryotes but their role and mechanism of action in apicomplexan parasites remain enigmatic. Here, we present a crystal structure of a unique homodimeric CP from the rodent malaria parasite Plasmodium berghei. In addition, we compare homo- and heterodimeric arrangements of P. berghei CPs (PbCPs) in solution. We complement our findings by describing the regulatory effects of PbCPs on heterologous skeletal muscle α-actin as well as parasite actin. Comprehensive kinetic and steadystate measurements show atypical regulation of actin dynamics; PbCPs facilitate rapid turnover of parasite actin I without affecting the apparent critical concentration. Possibly to rescue actin filament capping in life cycle stages where the CP β-subunit is downregulated, homo- and heterodimeric PbCPs show redundant effects in vitro. However, our data suggest that homodimers may in addition influence actin kinetics by recruiting lateral actin dimers. This unusual function could arise from the absence of a β-subunit, as the asymmetric PbCP homodimer lacks the structural elements essential for canonical barbed end interactions, suggesting a novel CP binding mode. These findings facilitate further studies aimed at elucidating the precise actin filament capping mechanism in Plasmodium and the eligibility of PbCPs as drug targets against malaria.Significance statementMalaria parasites of the genus Plasmodium display a unique form of gliding motility, which depends on an unconventional actomyosin motor. Actin capping proteins (CPs) play a major role in regulating parasite motility. Here, we describe a unique Plasmodium berghei CP (PbCP) system, behaving contradictory to canonical heterodimeric CPs, more suited to regulate the fast dynamics of the parasite actin system. We present the crystal structure of a distinctive homodimeric form of PbCP and extensive biochemical data, describing the atypical behavior of each PbCP form. The PbCP homodimer displays capping even in the absence of canonical conserved structural elements, suggesting a novel actin-CP interaction mode. These distinct structural properties could provide opportunities for drug design against malaria.

scholarly journals Structure and Function of an Atypical Homodimeric Actin Capping Protein from the Malaria Parasite

2021 ◽  
Author(s):  
Ábris Ádám Bendes ◽  
Petri Kursula ◽  
Inari Kursula
Keyword(s):  
Life Cycle ◽  
Actin Filament ◽  
Malaria Parasite ◽  
Critical Concentration ◽  
Binding Mode ◽  
Actin Dynamics ◽  
Β Subunit ◽  
Parasite Life Cycle ◽  
Capping Protein ◽  
Actin Capping Protein

Abstract Apicomplexan parasites, such as Plasmodium spp., rely on an unusual actomyosin motor, termed glideosome, for motility and host cell invasion. The actin filaments are maintained by a small set of essential regulators, which provide control over actin dynamics in the different stages of the parasite life cycle. Actin filament capping proteins (CPs) are indispensable heterodimeric regulators of actin dynamics. CPs have been extensively characterized in higher eukaryotes, but their role and functional mechanism in Apicomplexa remain enigmatic. Here, we present the first crystal structure of a homodimeric CP from the malaria parasite and compare the homo- and heterodimeric CP structures in detail. Despite retaining several characteristics of a canonical CP, the homodimeric Plasmodium berghei (Pb)CP exhibits crucial differences to the canonical heterodimers. Both homo- and heterodimeric PbCPs regulate actin dynamics in an atypical manner, facilitating rapid turnover of parasite actin, without affecting its critical concentration. Homo- and heterodimeric PbCPs show partially redundant activities, possibly to rescue actin filament capping in life cycle stages where the β-subunit is downregulated,. Our data suggest that the homodimeric PbCP also influences actin kinetics by recruiting lateral actin dimers. This unusual function could arise from the absence of a β-subunit, as the asymmetric PbCP homodimer lacks structural elements essential for canonical barbed end interactions suggesting a novel CP binding mode. These findings will facilitate further studies aimed at elucidating the precise actin filament capping mechanism in Plasmodium.

scholarly journals Functional homo- and heterodimeric actin capping proteins from the malaria parasite

2020 ◽  
Vol 525 (3) ◽  
pp. 681-686
Author(s):  
Ábris Ádám Bendes ◽  
Moon Chatterjee ◽  
Benjamin Götte ◽  
Petri Kursula ◽  
Inari Kursula
Keyword(s):  
Malaria Parasite ◽  
Capping Proteins ◽  
Actin Capping

scholarly journals Crystal structure of human V-1 in the apo form

2021 ◽  
Vol 77 (1) ◽  
pp. 13-21
Author(s):  
Shuichi Takeda ◽  
Ryotaro Koike ◽  
Takayuki Nagae ◽  
Ikuko Fujiwara ◽  
Akihiro Narita ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Actin Dynamics ◽  
Side Chain ◽  
Capping Protein ◽  
Actin Capping Protein ◽  
Large Conformational Change ◽  
Actin Capping ◽  
Atom Motion ◽  
Specific Ligand

V-1, also known as myotrophin, is a 13 kDa ankyrin-repeat protein that binds and inhibits the heterodimeric actin capping protein (CP), which is a key regulator of cytoskeletal actin dynamics. The crystal structure of V-1 in complex with CP revealed that V-1 recognizes CP via residues spanning several ankyrin repeats. Here, the crystal structure of human V-1 is reported in the absence of the specific ligand at 2.3 Å resolution. In the asymmetric unit, the crystal contains two V-1 monomers that exhibit nearly identical structures (Cα r.m.s.d. of 0.47 Å). The overall structures of the two apo V-1 chains are also highly similar to that of CP-bound V-1 (Cα r.m.s.d.s of <0.50 Å), indicating that CP does not induce a large conformational change in V-1. Detailed structural comparisons using the computational program All Atom Motion Tree revealed that CP binding can be accomplished by minor side-chain rearrangements of several residues. These findings are consistent with the known biological role of V-1, in which it globally inhibits CP in the cytoplasm.

scholarly journals Gliding motility protein LIMP promotes optimal mosquito midgut traversal and infection by Plasmodium berghei

2021 ◽  
Vol 241 ◽  
pp. 111347
Author(s):  
Saskia Egarter ◽  
Jorge M. Santos ◽  
Jessica Kehrer ◽  
Julia Sattler ◽  
Friedrich Frischknecht ◽  
...  
Keyword(s):  
Plasmodium Berghei ◽  
Gliding Motility ◽  
Mosquito Midgut

Histochemical observations on the exoerythrocytic malaria parasite Plasmodium berghei in rat liver

1984 ◽  
Vol 81 (5) ◽  
pp. 417-425 ◽  
Author(s):  
J. F. G. M. Meis ◽  
J. P. Verhave ◽  
P. Wirtz ◽  
J. H. E. Th. Meuwissen
Keyword(s):  
Rat Liver ◽  
Plasmodium Berghei ◽  
Malaria Parasite ◽  
Parasite Plasmodium

scholarly journals Anopheles gambiae APL1 Is a Family of Variable LRR Proteins Required for Rel1-Mediated Protection from the Malaria Parasite, Plasmodium berghei

PLoS ONE ◽  
2008 ◽  
Vol 3 (11) ◽  
pp. e3672 ◽  
Author(s):  
Michelle M. Riehle ◽  
Jiannong Xu ◽  
Brian P. Lazzaro ◽  
Susan M. Rottschaefer ◽  
Boubacar Coulibaly ◽  
...  
Keyword(s):  
Anopheles Gambiae ◽  
Plasmodium Berghei ◽  
Malaria Parasite ◽  
Parasite Plasmodium

scholarly journals Tropomyosin inhibits ADF/cofilin-dependent actin filament dynamics

2002 ◽  
Vol 156 (6) ◽  
pp. 1065-1076 ◽  
Author(s):  
Shoichiro Ono ◽  
Kanako Ono
Keyword(s):  
Actin Filament ◽  
Actin Filaments ◽  
Actin Polymerization ◽  
Biological Properties ◽  
Actin Dynamics ◽  
Background Suppression ◽  
Thin Filaments ◽  
Actin Organization ◽  
C Elegans ◽  
Filament Dynamics

Tropomyosin binds to actin filaments and is implicated in stabilization of actin cytoskeleton. We examined biochemical and cell biological properties of Caenorhabditis elegans tropomyosin (CeTM) and obtained evidence that CeTM is antagonistic to ADF/cofilin-dependent actin filament dynamics. We purified CeTM, actin, and UNC-60B (a muscle-specific ADF/cofilin isoform), all of which are derived from C. elegans, and showed that CeTM and UNC-60B bound to F-actin in a mutually exclusive manner. CeTM inhibited UNC-60B–induced actin depolymerization and enhancement of actin polymerization. Within isolated native thin filaments, actin and CeTM were detected as major components, whereas UNC-60B was present at a trace amount. Purified UNC-60B was unable to interact with the native thin filaments unless CeTM and other associated proteins were removed by high-salt extraction. Purified CeTM was sufficient to restore the resistance of the salt-extracted filaments from UNC-60B. In muscle cells, CeTM and UNC-60B were localized in different patterns. Suppression of CeTM by RNA interference resulted in disorganized actin filaments and paralyzed worms in wild-type background. However, in an ADF/cofilin mutant background, suppression of CeTM did not worsen actin organization and worm motility. These results suggest that tropomyosin is a physiological inhibitor of ADF/cofilin-dependent actin dynamics.

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