Abundance of intrinsically unstructured proteins in P. falciparum and other apicomplexan parasite proteomes.

Preliminary sequence analysis of Plasmodium falciparum has shown that the proteome of this organism is enriched in intrinsically unstructured proteins (IUPs), which are either completely disordered or contain large disordered regions. IUPs have been characterized as a unique class of proteins that plays an important role in biology and disease. In this study, the IUP contents in the proteomes of apicomplexan parasites, especially the proteome of P. falciparum and its various life cycle stages, have been evaluated with DisEMBL-1.4. Compared with other proteomes, apicomplexan species are extremely abundant in proteins containing long disordered regions, and the IUP contents in mammalian Plasmodium species are higher than in most other apicomplexan parasites. The proteome of the P. falciparum sporozoite appears to be distinct from the other life cycle stages in having an even higher content of disordered proteins. The abundance of IUPs in the P. falciparum proteome correlates with its enrichment in repetitive sequences. The structural plasticity of IUPs, which allows promiscuous binding interactions, may favour parasite survival both by inhibiting the generation of effective high affinity antibody responses and by facilitating the interactions with host molecules necessary for attachment and invasion of host cells.

[1]  B. Gamain,et al.  Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family. , 2000, Molecular and biochemical parasitology.

[2]  P. Romero,et al.  Sequence complexity of disordered protein , 2001, Proteins.

[3]  Burkhard Rost,et al.  NORSp: predictions of long regions without regular secondary structure , 2003, Nucleic Acids Res..

[4]  P. Karplus,et al.  Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and inhibitor development. , 2003, Journal of molecular biology.

[5]  W. Kabsch,et al.  Dictionary of protein secondary structure: Pattern recognition of hydrogen‐bonded and geometrical features , 1983, Biopolymers.

[6]  R. Anders,et al.  Conservation of structural motifs and antigenic diversity in the Plasmodium falciparum merozoite surface protein-3 (MSP-3). , 1997, Molecular and biochemical parasitology.

[7]  P. Tompa,et al.  Structural disorder throws new light on moonlighting. , 2005, Trends in biochemical sciences.

[8]  Neil Hall,et al.  Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry , 2002, Nature.

[9]  D. Eisenberg,et al.  A census of protein repeats. , 1999, Journal of molecular biology.

[10]  Danny W. Wilson,et al.  Ten families of variant genes encoded in subtelomeric regions of multiple chromosomes of Plasmodium chabaudi, a malaria species that undergoes antigenic variation in the laboratory mouse , 2003, Molecular microbiology.

[11]  R. Nussinov,et al.  Extended disordered proteins: targeting function with less scaffold. , 2003, Trends in biochemical sciences.

[12]  Neil Hall,et al.  The genome of model malaria parasites, and comparative genomics. , 2005, Current issues in molecular biology.

[13]  E V Koonin,et al.  Chromosome 2 sequence of the human malaria parasite Plasmodium falciparum. , 1998, Science.

[14]  P. Tompa.  Intrinsically unstructured proteins. , 2002, Trends in biochemical sciences.

[15]  M. Foley,et al.  Molecular variation in a novel polymorphic antigen associated with Plasmodium falciparum merozoites. , 1994, Molecular and biochemical parasitology.

[16]  C. Janse,et al.  Plasmodium post-genomics: better the bug you know? , 2006, Nature Reviews Microbiology.

[17]  C. Brown,et al.  Intrinsic protein disorder in complete genomes. , 2000, Genome informatics. Workshop on Genome Informatics.

[18]  John R Yates,et al.  A Comprehensive Survey of the Plasmodium Life Cycle by Genomic, Transcriptomic, and Proteomic Analyses , 2005, Science.

[19]  M. Wahlgren,et al.  Malaria A blueprint of ‘bad air’ , 1999, Nature.

[20]  S. Vucetic,et al.  Flavors of protein disorder , 2003, Proteins.

[21]  Alan W. Thomas,et al.  Crystal Structure of the Malaria Vaccine Candidate Apical Membrane Antigen 1 , 2005, Science.

[22]  R. Gwilliam,et al.  The complete nucleotide sequence of chromosome 3 of Plasmodium falciparum , 1999, Nature.

[23]  M. Foley,et al.  Structure of domain III of the blood-stage malaria vaccine candidate, Plasmodium falciparum apical membrane antigen 1 (AMA1). , 2002, Journal of molecular biology.

[24]  L. Aravind,et al.  Plasmodium Biology Genomic Gleanings , 2003, Cell.

[25]  N. Hall,et al.  Comparative genomics of malaria parasites. , 2005, Current opinion in genetics & development.

[26]  Chris Sander,et al.  CAST: an iterative algorithm for the complexity analysis of sequence tracts , 2000, Bioinform..

[27]  Thomas A. Smith,et al.  Safety and immunogenicity of a three-component blood-stage malaria vaccine (MSP1, MSP2, RESA) against Plasmodium falciparum in Papua New Guinean children. , 2003, Vaccine.

[28]  David T. Jones,et al.  Prediction of disordered regions in proteins from position specific score matrices , 2003, Proteins.

[29]  John C. Wootton,et al.  Statistics of Local Complexity in Amino Acid Sequences and Sequence Databases , 1993, Comput. Chem..

[30]  A. Cowman,et al.  Changes in repeat number, sequence, and reading frame in S-antigen genes of Plasmodium falciparum , 1987, Molecular and cellular biology.

[31]  R. Coppel,et al.  Repetitive proteins and genes of malaria. , 1987, Annual review of microbiology.

[32]  V. Uversky.  Intrinsically Disordered Proteins , 2000 .

[33]  P. Radivojac,et al.  Protein flexibility and intrinsic disorder , 2004, Protein science : a publication of the Protein Society.

[34]  R. Durrett,et al.  Equilibrium distributions of microsatellite repeat length resulting from a balance between slippage events and point mutations. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[35]  R. Coppel,et al.  Antigens with repeated amino acid sequences from the asexual blood stages of Plasmodium falciparum. , 1988, Progress in allergy.

[36]  Robert M. MacCallum,et al.  Striped sheets and protein contact prediction , 2004, ISMB/ECCB.

[37]  Barbara J. B. Johnson,et al.  BBK32, a Fibronectin Binding MSCRAMM from Borrelia burgdorferi, Contains a Disordered Region That Undergoes a Conformational Change on Ligand Binding* , 2004, Journal of Biological Chemistry.

[38]  Christopher J. Oldfield,et al.  Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling , 2005, Journal of molecular recognition : JMR.

[39]  Thomas A. Smith,et al.  A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea. , 2002, The Journal of infectious diseases.

[40]  Fran Lewitter,et al.  Intragenic tandem repeats generate functional variability , 2005, Nature Genetics.

[41]  Peter Tompa,et al.  The role of structural disorder in the function of RNA and protein chaperones , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  C. Withers-Martinez,et al.  Unique insertions within Plasmodium falciparum subtilisin-like protease-1 are crucial for enzyme maturation and activity. , 2005, Molecular and biochemical parasitology.

[43]  S. Karlin,et al.  Conservation among HSP60 sequences in relation to structure, function, and evolution , 2008, Protein science : a publication of the Protein Society.

[44]  D. Conway,et al.  A large focus of naturally acquired Plasmodium knowlesi infections in human beings , 2004, The Lancet.

[45]  Mark A DePristo,et al.  On the abundance, amino acid composition, and evolutionary dynamics of low-complexity regions in proteins. , 2006, Gene.

[46]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[47]  C. Dobson,et al.  Structural and dynamical characterization of a biologically active unfolded fibronectin-binding protein from Staphylococcus aureus. , 1998, Biochemistry.

[48]  M. Vihinen,et al.  Accuracy of protein flexibility predictions , 1994, Proteins.

[49]  David L. Tabb,et al.  A proteomic view of the Plasmodium falciparum life cycle , 2002, Nature.

[50]  O. Sodeinde,et al.  A unique insertion in Plasmodium berghei glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase: evolutionary and functional studies. , 2003, Molecular and biochemical parasitology.

[51]  P. Tompa,et al.  The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins. , 2005, Journal of molecular biology.

[52]  Debasis Dash,et al.  Comparative analysis of protein unfoldedness in human housekeeping and non-housekeeping proteins , 2004, Bioinform..

[53]  T. Gibson,et al.  Protein disorder prediction: implications for structural proteomics. , 2003, Structure.

[54]  P. Tompa.  Intrinsically unstructured proteins evolve by repeat expansion , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[55]  D. Forsdyke,et al.  Low-complexity segments in Plasmodium falciparum proteins are primarily nucleic acid level adaptations. , 2003, Molecular and biochemical parasitology.

[56]  Yingyao Zhou,et al.  Global analysis of transcript and protein levels across the Plasmodium falciparum life cycle. , 2004, Genome research.

[57]  Wim G J Hol,et al.  Heterologous expression of proteins from Plasmodium falciparum: results from 1000 genes. , 2006, Molecular and biochemical parasitology.

[58]  G. Singh,et al.  Hyper-expansion of asparagines correlates with an abundance of proteins with prion-like domains in Plasmodium falciparum. , 2004, Molecular and biochemical parasitology.

[59]  Aditi Gupta,et al.  Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[60]  C. A. Andersen,et al.  Continuum secondary structure captures protein flexibility. , 2002, Structure.

[61]  Liisa Holm,et al.  Rapid automatic detection and alignment of repeats in protein sequences , 2000, Proteins.

[62]  V. Uversky,et al.  Why are “natively unfolded” proteins unstructured under physiologic conditions? , 2000, Proteins.

[63]  R. Coppel,et al.  Structural diversity in the Plasmodium falciparum merozoite surface antigen 2. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[64]  Jaime Prilusky,et al.  FoldIndex copyright: a simple tool to predict whether a given protein sequence is intrinsically unfolded , 2005, Bioinform..

[65]  H. Dyson,et al.  Intrinsically unstructured proteins and their functions , 2005, Nature Reviews Molecular Cell Biology.

[66]  R. Anders,et al.  Multiple cross‐reactivities amongst antigens of Plasmodium falciparum impair the development of protective immunity against malaria , 1986, Parasite immunology.

[67]  E. Pizzi,et al.  Low-complexity regions in Plasmodium falciparum proteins. , 2001, Genome research.

[68]  K. Namba.  Roles of partly unfolded conformations in macromolecular self‐assembly , 2001, Genes to cells : devoted to molecular & cellular mechanisms.

[69]  J. S. Sodhi,et al.  Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. , 2004, Journal of molecular biology.

[70]  Q. Bassat,et al.  Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial , 2005, The Lancet.

[71]  R. Norton,et al.  Structure and inter-domain interactions of domain II from the blood-stage malarial protein, apical membrane antigen 1. , 2005, Journal of molecular biology.

[72]  Jonathan E. Allen,et al.  Genome sequence of the human malaria parasite Plasmodium falciparum , 2002, Nature.

[73]  B. Rost,et al.  Loopy proteins appear conserved in evolution. , 2002, Journal of molecular biology.

[74]  L. Brocchieri,et al.  Low-complexity regions in Plasmodium proteins: in search of a function. , 2001, Genome research.