Structural Insights into the Protease-like Antigen Plasmodium falciparum SERA5 and Its Noncanonical Active-Site Serine

Hodder, Anthony N.; Malby, Robyn L.; Clarke, Oliver; Fairlie, W. Douglas; Colman, Peter M.; Crabb, Brendan S.; Smith, Brian J.

doi:10.1016/j.jmb.2009.07.007

Cited by 37 publications

(56 citation statements)

References 62 publications

(72 reference statements)

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“…Rabbit antibodies to MSP1-19 (64) were kindly provided by Brendan Crabb, Burnet Institute. The SERA4 central domain was prepared in a manner similar to that for the central domain of SERA5 (65,66), and the in vitro refolded protein was used to produce antibodies in rabbits. The cysteine-rich region of the C-terminal fragment of SERA5 (R914 and V997) was oxidatively refolded in a manner similar to that for the SERA5 central domain.…”

Section: Methodsmentioning

confidence: 99%

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

et al. 2014

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e Plasmodium falciparum causes malaria disease during the asexual blood stages of infection when merozoites invade erythrocytes and replicate. Merozoite surface proteins (MSPs) are proposed to play a role in the initial binding of merozoites to erythrocytes, but precise roles remain undefined. Based on electron microscopy studies of invading Plasmodium merozoites, it is proposed that the majority of MSPs are cleaved and shed from the surface during invasion, perhaps to release receptor-ligand interactions. In this study, we demonstrate that there is not universal cleavage of MSPs during invasion. Instead, there is sequential and coordinated cleavage and shedding of proteins, indicating a diversity of roles for surface proteins during and after invasion. While MSP1 and peripheral surface proteins such as MSP3, MSP7, serine repeat antigen 4 (SERA4), and SERA5 are cleaved and shed at the tight junction between the invading merozoite and erythrocyte, the glycosylphosphatidylinositol (GPI)-anchored proteins MSP2 and MSP4 are carried into the erythrocyte without detectable processing. Following invasion, MSP2 rapidly degrades within 10 min, whereas MSP4 is maintained for hours. This suggests that while some proteins that are shed upon invasion may have roles in initial contact steps, others function during invasion and are then rapidly degraded, whereas others are internalized for roles during intraerythrocytic development. Interestingly, anti-MSP2 antibodies did not inhibit invasion and instead were carried into erythrocytes and maintained for approximately 20 h without inhibiting parasite development. These findings provide new insights into the mechanisms of invasion and knowledge to advance the development of new drugs and vaccines against malaria.

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Section: Methodsmentioning

confidence: 99%

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

et al. 2014

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“…Serine repeat antigen 5 contains cHABPs 6746 ( 581 DQGNCDTSWIFASKYHLETI 600 ) and 6754 ( 741 KKVQNLCGDDTADHAVNIVG 760 ) in its 50 kDa fragment, forming a trough or channel stabilised by an H-bond where non-canonical cysteine protease enzymatic activity is located ( Figure 3B, pale blue and dark yellow) (Hodder et al, 2009).…”

Section: Escape Mechanismmentioning

confidence: 99%

“…(A) SPECT-1 (PDB accession code 4U5A) (Hamaoka and Ghosh, 2014) and cHABPs 33372 (dark yellow) and 33375 (blue). (B) SERA-5 recombinant fragment (PDB code 3CH2) (Hodder et al, 2009) and the localisation of cHABPs 6746 (in dark yellow) and 6754 (in blue) whose Hbonds form the catalytic triad. RIGHT panel: (A, B, C and D) Representation of variability using Shannon's diversity index for each amino acid in the protein sequence.…”

Section: Escape Mechanismmentioning

confidence: 99%

“…KYHLETI 600 ) and 6754 ( 741 KKVQNLCGDDTAD HAVNIVG 760 ) forming H-bonds as part of an enzymatic triad and constituting the noncanonical serine protease active site (Hodder et al, 2009). There are also intercalated hypervariable regions, as occurs with Rh5 cHABPs 36727 ( 201 GKYIAVDAFIKKINET YDKV 220 ) and 36735 ( 361 DEYIHKLILSVKSKN LNKDL 380 ) establishing contact with basigin (Chen, L. et al, 2014), and another such as MSP-1 cHABP 5501 ( 1544 MLNISQHQCVKKQC PQNS 1561 ), having a variable aa in its C-terminus and interacting with the band 3 sequence (Pizarro et al, 2003).…”

Section: Escape Mechanismmentioning

confidence: 99%

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Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

Patarroyo¹,

Aza-Conde²,

Moreno-Vranich³

et al. 2017

Current Issues in Molecular Biology

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Like Thomas Hardy's famous novel Far from the Madding Crowd, Plasmodium falciparum parasites display their most relevant survival structures (proteins) involved in host cell invasion far away from the immune system's susceptible regions, displaying tremendous genetic variability, to attract the immune response and escape immune pressure. The 3D structure localisation of the conserved amino acid sequences of this deadly parasite's most relevant proteins involved in host cell invasion, as well as the location of the highly polymorphic, h i g h l y i m m u n o g e n i c r e g i o n s , c l e a r l y demonstrates that such structures are far apart, sometimes 90° to 180° opposite, thereby rendering the immune response useless. It is also shown here that these conserved, f u n c t i o n a l l y -r e l e v a n t s t r u c t u r e s a r e immunologically silent, since no immune response has been induced.

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“…In the C-terminal cysteine rich conserved domain, seven cysteine residues are perfectly conserved in all SERA genes. The pro-enzyme and enzyme domains of P. falciparum SERA5 was identified by functional genetic and structural analyses (Hodder et al, 2003(Hodder et al, , 2009). These domains, corresponding to P50 in Fig.…”

Section: Primary Structure Of Sera Molecules and Genesmentioning

confidence: 99%

Clues to Evolution of the SERA Multigene Family in the Genus Plasmodium

Arisue¹,

Palacpac²,

Tanabe³

et al. 2011

Gene Duplication

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Structural Insights into the Protease-like Antigen Plasmodium falciparum SERA5 and Its Noncanonical Active-Site Serine

Cited by 37 publications

References 62 publications

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

Sequential Processing of Merozoite Surface Proteins during and after Erythrocyte Invasion by Plasmodium falciparum

Far from the Madding Crowd: the Molecular Basis for Immunological Escape ofPlasmodium falciparum

Clues to Evolution of the SERA Multigene Family in the Genus Plasmodium

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