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- Data-Mining Approaches Reveal Hidden Families of Proteases in the Genome of Malaria Parasite


Table 1. Ninety-two (92) P. falciparum Protease Homologs Predicted From Comparative Genomic Analysis

Catalytic class Protease family Protease nomenclature Gene ID Protease homolog with highest BLAST score
Aspartic A1 PM I PF14_0076 P39898 (P. falciparum, PM I) 0 PF00026 (eukaryotic  asp protease) 1.5e-59 +
PM II PF14_0077 P46925 (P. falciparum, PM II) 0 PF00026 (eukaryotic  asp protease) 8.9e-52
HAP(PM III) PF14_0078 CAB40630 (P. falciparum, HAP) 0 PF00026 (eukaryotic  asp protease) 3.3e-30 +
PM IV PF14_0075 AAC15794 (P. malariae, PM) 0 PF00026 (eukaryotic  asp protease) 5.1e-56
PM V PF13_0133 Q05744 (Chicken, Cathepsin D) 9e-08 PF00026 (eukaryotic  asp protease) 0.00037 +
PM VI PFC0495w CAC20153 (Eimeria tenella,  eimepsin) 2e-99 PF00026 (eukaryotic  asp protease) 1.1e-40
PM VII PF10_0329 CAC20153 (Eimeria tenella,  eimepsin) 8e-28 PF00026 (eukaryotic  asp protease) 1.3e-11 +
PM VIII PF14_0623 CAC20153 (Eimeria tenella,  eimepsin) 1e-35 PF00026 (eukaryotic  asp protease) 7.5e-11
PM IX PF14_0281 AAD56283 (Pseudopleuronectes  americanus, pepsinogen A  form IIa) 1e-33 PF00026 (eukaryotic  asp protease) 4.5e-26
PM X PF08_0108 AAA31096 (Pig, pepsinogen A) 1e-42 PF00026 (eukaryotic  asp protease) 2.5e-26 +
Cysteine C1 Falcipain-1 PF14_0553 P25805 (P. falciparum,  falcipain-1) 0 PF00112 (Papain  family) 9.5e-92
Falcipain-2 PF11_0165 AAF63497 (P. falciparum,  falcipain 2) 0 PF00112 (Papain  family) 3.0e-84 +
Falcipain-3 PF11_0162 AAF86352 (P. falciparum,  falcipain-3) 0 PF00112 (Papain  family) 4.8e-79
Papain PF11_0161 AAF97809 (P. falciparum,  Falcipain 2) 1e-134 PF00112 (Papain  family) 8.8e-84 +
DPP I PFL2290w AAD02704 (Dog, DPP I) 5e-30 PF00112 (Papain  family) 9.9e-16
DPP I PFD0230c AAD02704 (Dog, DPP I) 6e-06 PF00112 (Papain  family) 2.7e-05 +
Cathepsin C PF11_0174 AAL48191 (Human,  Cathepsin C) 5e-23 PF00112 (Papain  family) 3.3e-14 +
SERA PFB0360c H71617 (P. falciparum, SERA) 0 PF00112 (Papain  family) 2.1e-51
SERA PFB0325c F71617 (P. falciparum, SERA) 0 PF00112 (Papain  family) 2.9e-10
SERA PFB0330c G71617 (P. falciparum, SERA) 0 PF00112 (Papain  family) 2.9e-46
SERA PFB0335c H71617 (P. falciparum, SERA) 0 PF00112 (Papain  family) 3.4e-16
SERA PFB0340c B71617 (P. falciparum, SERA) 0 PF00112 (Papain  family) 1.5e-53
SERA PFB0345c C71617 (P. falciparum, SERA) 0 PF00112 (Papain  family) 1.2e-47
SERA PFB0350c D71617 (P. falciparum, SERA) 0 PF00112 (Papain  family) 8.8e-51
SERA PFB0355c H71617 (P. falciparum, SERA) 0 PF00112 (Papain  family) 1.5e-49
Papain PFI0135c G71617 (P. falciparum, SERA) 1e-177 PF00112 (Papain  family) 2.2e-34
C2 Calpain MAL13P1.310 NP_497964 (C. elegans,  Calpain) 2e-35 PF00648 (Calpain  family) 8.0e-13
C12 UCH1 PF14_0577 BAB47136 (Rat, UCH 13) 5e-31 PF01088 (UCH 1) 1.3e-37
UCH1 PF11_0177 NP_062508 (Mouse, UCH37) 6e-30 PF01088 (UCH 1) 1.5e-17
C13 GPI8p  transamidase PF11_0298 CAB96076 (P. falciparum,  GPI8p transamidase) 1e-179 PF01650 (Peptidase  C13) 2.7e-13 +
C14 Metacaspase PF13_0289 CAD24804 (T. brucei,  metacaspase) 5e-32 No hits
C19 UCH2 PFA0220w NP_566486 (Arabidopsis,  UBP25) 1e-12 PF00442 (UCH2) 1.2e-09
UCH2 PFD0165w O57429 (Chicken, UCH2) 5e-13 PF00442 (UCH2) PF00443 (UCH2) 1.9e-06 9.2e-07
UCH2 PFD0680c AAG42755 (Arabidopsis,  UBP14) 1e-34 PR00442 (UCH2) 8.5e-11
UCH2 PFE1355c NP_566680 (Arabidopsis,  UBP7) 3e-30 PF00442 (UCH2) PF00443 (UCH2) 7.5e-07 1.9e-14
UCH2 PFE0835w 094966 (Human, UBP19) 3e-51 PF00442 (UCH2) PF00443 (UCH2) 1.8e-11 1.7e-20
UCH2 MAL7P1.147 NP_568171 (Arabidopsis,  UBP12) 1e-54 PF00442 (UCH2) PF00443 (UCH2) 3.7e-10 1.9e-16
UCH2 PFI0225w AAC68865 (Chicken, UBP66) 1e-18 PF00442 (UCH2) 9.9e-23
UCH2 PF13_0096 NP_494298 (C. elegans, UBP) 5e-58 PF00442 (UCH2) PF00443 (UCH2) 4.3e-08 0.00048
UCH2 PF14_0145 T41069 (Fission yeast, UCH) 1e-20 PF00442 (UCH2) PF00443 (UCH2) 4.8e-05 3.1e-08
C48 Sumo1 protease PFL1635w XP_128236 (Mouse, SUMO  protease) 7e-33 PF02902 (Ulp1  protease) 2.3e-38
Ulp2 peptidase MAL8P1.157 O13769 (Fission yeast, Ulp2) 1e-06 PF02902 (Ulp1  protease) 9.2e-07
C56 DJ-1 peptidase MAL6P1.153 BAB79527 (Chicken, DJ-1  protease) 6e-16 PF01965 (DJ-1/PfpI  protease) 8.1e-18
Metallo M1 AMPN MAL13P1.56 O96935 (P. falciparum,  M1 peptidase) 0 PF01433 (Peptidase  family M1) 6.2e-74
M3 Dcp PF10-0058 NP_601500 (Corynebacterium  glutamicum, Zn-dependent  peptidases) 1e-04 PF01432 (Peptidase  family M3) 6.4e-10
Neurolysin MAL13P1.184 Q02038 (Pig, neurolysin) 4e-09 PF01432 (Peptidase  family M3) 1.8e-07
M16 MPPa PFE1155c AAF00541 (Toxoplama gondii,  MPPa) 1e-109 PF00675 (Insulinase,  family M16) 6.4e-19
MPPb PFI1625c AAK51086 (Avicennia  marina, MPPb) 1e-108 PF00675 (Insulinase,  family M16) 1.3e-55
M16 peptidase PF11_0189 NP_593544 (yeast  metallopeptidase) 1e-29 PF00675 (Insulinase,  family M16) 0.0076
Insulysin PF11_0226 P35559 (Rat, Insulysin) 3e-10 PF00675 (Insulinase,  family M16) 1.0e-05
Falcilysin PF13_0322 AAF06062 (P. falciparum,   falcilysin) 0 PF00675 (Insulinase,  family M16) 0.19
Pitrilysin PF14_0382 T06521 (Pea pitrilysin) 5e-27 PF00675 (Insulinase,  family M16) 0.0018
M17 AMPL PF14_0439 NP_194821 (Arabidopsis  AMPL) 2e-83 PF00883 (Peptidase  family M17) 9e-150
M18 DNPE PFI1570c AAL16034 (Coccidioides  immitis, DNPE) 7e-55 PF02127 (Peptidase  family M18) 3.6e-31
M22 GCP PF10_0299 NP_194003 (Arabidopsis  GCP) 4e-54 PF00814 (Glycoprotease family) 1.3e-53
M24A AMPM PFE1360c AAG33975 (Arabidopsis,  AMPM) 3e-61 PF00557 (Peptidase  family M24) 2.5e-48
AMPM MAL8P1.140 P53582 (Human, AMP1) 1e-26 PF00557 (Peptidase  family M24) 9.1e-06 +
AMPM PF10_0150 P53582 (Human, AMP1) 1e-104 PF00557 (Peptidase  family M24) 5.4e-67
AMPM PF14_0327 AAL76285 (P. falciparum,  AMPM2) 0 PF00557 (Peptidase  family M24) 8.7e-50
M24B AMPP PF14_0517 CAC59823 (Tomato, AMPP) 3e-85 PF00557 (Peptidase  family M24) 2.8e-07
M41 Ftsh peptidase PF11_0203 NP_006787 (Human, AFG3) 1e-163 PF01434 (Peptidase  family M41) PF00004 (AAA) 2.6e-80 4.0e-80
Ftsh peptidase PFL1925w NP_422020 (Caulobacter  crescentus, cell division  protein FtsH) 1e-122 PF01434 (Peptidase  family M41) PF00004 (AAA) 3.2e-93 5.7e-90
Ftsh peptidase PF14_0616 NP_568787 (Arabidopsis, FtsH) 1e-141 PF01434 (Peptidase family M41) 2.7e-69
PF00004 (AAA 9.9e-85
Serine S1 DegP protease MAL8P1.126 NP_568577 (Arabidopsis, DegP protease) 4e-52 PF00089 (Trypsin) 1.8e-07
Neurotypsin-like PF14_0067 BAA23986 (Mouse, neurotrypsin) 7e-17 PF01477 (PLAT/LH2 domain) 1.4e-09
S8 Subtilase-1 PFE0370c CAA05627 (P. falciparum, subtilase-1) 0 PF00082 (Subtilase family) 2.6e-15
Subtilase-2 PF11_0381 CAB43592 (P. falciparum, Subtilase-2) 0 PF00082 (Subtilase family) 1.6e-35
Subtilase-like PFE0355c CAA05627 (P. falciparum, subtilase-1) 2e-22 PF00082 (Subtilase family) 5.6e-19
S9 ACPH PFC0950c P13676 (Rat, ACPH) 1e-17 PF00561 ({alpha}/{beta} hydrolase fold) 0.021
S14 Clp PFC0310c P54416 (Synechocystis sp Clp1) 6e-42 PF00574 (Clp protease) 1.8e-65 +
Clp PF14_0348 NP_567521 (Arabidopsis clp) 2e-29 PF00574 (Clp protease) 3.0e-37 +
ClpB PF08_0063 AAA88777 (P. berghei, ClpB) 0 PF00574 (Clp protease) 1.0-16
ClpB PF14_0063 NP_439019 (Haemophilus influenzae ClpB) 3e-95 PF00004 (AAA) 7.1e-06 +
ClpC PF11_0175 T07807 (Soybean clp) 1e-154 PF00574 (Clp protease) 0.0026
S16 Lon PF14_0147 AAA61616 (Human, Lon) 4e-53 PF00004 (AAA) 1.4e-17
S26A SP1 PF13_0118 T40251 (Fission yeast, IMP) 2e-10 PF00461 (Signal peptidase) 0.055
S26B signalase MAL13P1.167 AAD19813 (Drosophila, signalase SPC21) 3e-46 PF00461 (Signal peptidase) 3.7e-19
S54 Rhomboid PFE0340c NP_523536 (Drosophila, rhomboid-5) 6e-07 PF01694 (Rhomboid family) 5.5e-27
Rhomboid MAL8P1.16 NP_654179 (Bacillus anthracis rhomboid) 2e-07 PF01694 (Rhomboid family) 3.8e-27
Threonine T1 Proteasome {alpha}1 PF14_0716 P92188 (Trypanosoma cruzi, {alpha}1) 8e-57 PF00227 (Proteasome) 7.7e-39
Proteasome {alpha}2 MAL6P1.88 O9LSU2 (Rice, {alpha}2) 3e-73 PF00227 (Proteasome) 1.4e-49
Proteasome {alpha}3 PFC0745c O24362 (Spinach, {alpha}3) 3e-44 PF00227 (Proteasome) 2.0e-21
Proteasome {alpha}4 PF13_0282 O81148 (Arabidopsis, {alpha}4) 1e-64 PF00227 (Proteasome) 7.4e-47
Proteasome {alpha}5 PF07_0112 Q95083 (Drosophila,{alpha}5) 4e-70 PF00227 (Proteasome) 2.1e-47
Proteasome {alpha}6 MAL8P1.128 Q9LSU3 (Rice, {alpha}6) 4e-52 PF00227 (Proteasome) 2.8e-30
Proteasome {alpha}7 MAL13P1.270 O24616 (Arabidopsis, {alpha}7) 3e-66 PF00227 (Proteasome) 8.5e-43
Proteasome {beta}1 PFE0915c P42742 (Arabidopsis, {beta}1) 3e-44 PF00227 (Proteasome) 1.2e-39
Proteasome {beta}2 MAL8P1.142 Q9LST6 (Rice, {beta}2) 1e-35 PF00227 (Proteasome) 2.9e-17
Proteasome {beta}3 PFA0400c P25451 (Yeast, {beta}3) 8e-35 PF00227 (Proteasome) 1.5e-18
Proteasome {beta}4 PF14_0676 XP_079788 (Drosophila, {beta}4) 4e-36 PF00227 (Proteasome) 1.4e-22
Proteasome {beta}6 PFI1545c O43063 (Fission yeast, {beta}6) 4e-26 PF00227 (Proteasome) 1.1e-10

Proteasome {beta}7
Q99436 (Human, {beta}7)
PF00227 (Proteasome)

The cut-off criteria of E-score <= 1e-04 was employed to define protease homologs. The nomenclature of the protease family is: A1 (pepsin), C1 (papain), C2 (calpain), C12 (ubiquitin carboxyl-terminal hydrolase, family 1, UCH1), C13 (hemoglobinase), C14 (caspase), C19 (ubiquitin C-terminal hydrolase family 2, UCH2), C48 (Ubiquitin-like protease, Ulp), C56 (DJ-1 peptidase), M1 (alanyl aminopeptidase, AMPN), M3 (thimet oligopeptidase), M16 (pitrilysin and mitochondrial processing peptidase, MPP), M17 (leucyl aminopeptidase, AMPL), M18 (aspartyl aminopeptidase, DNPE), M22 (O-sialoglycoprotein endopeptidase, GCP), M24A (methionyl aminopeptidase, AMPM), M24B (X-Pro dipeptidase, AMPP), M41 (FtsH endopeptidase), S1 (trypsin), S8 (subtilsin), S9 (acylaminoacyl-peptidase, ACPH), S14 (clp), S16 (Lon protease, La), S26A (prokarytotic signal peptidase I, SP1), S26B (signalase), S54 (rhomboid), and T1 (threonine endopeptidase).

Abbreviations for proteases include: PM, plasmepsin; DPPI, dipeptidyl-peptidase I; UBP, ubiquitin-specific protease; IMP, mitochondrial inner membrane peptidase; SPC21, microsomal signal peptide 21 kDa subunit.

Previously characterized proteases with proteolytic activity are highlighted in bold. The 23 proteases predicted by the official annotation published in PlasmoDB are highlighted in italic.

Potential candidate proteases Calpain, Metacaspase, and Signal peptidase I (SP1) are highlighted in bold italic.

a ± indicate the gene is predicted to contain/not contain an apicoplast transit peptide.


Table 2. Expression Profiles of Putative Plasmodial Proteases

Gene ID Oligo Microarray (asyn)a Oligo Microarrayb
PF14_0076 21,915 7595 6935 + + +
PF14_0077 6544 6084 3034 + + +
PF14_0078 2981 16,185 7152 + + +
PF14_0075 20,151 20,979 21,090 + + +
PF13_0133 1521 5636 4810
PFC0495w* 454 +
PF10_0329 76
PF14_0623 215
PF14_0281 No oligo
PF08_0108 5561 2478 +
PF14_0553 3187 4947 4954 +
PF11_0165 8073 17,895 4771 +
PF11_0162 9302 4559 5676 + +
PF11_0161 2436 7318 2025 +
PFL2290w* 467 + +
PFD0230c 8342 2473 25,913 +
PF11_0174 19,855 36,201 19,570 + +
PFB0360c 376
PFB0325c* 179 +
PFB0330c 2415 2238 5476 + +
PFB0335c 3428 1695 4803
PFB0340c 28,613 13,254 59,511 + +
PFB0345c 2273 3115 10,053 +
PFB0350c 4572 6320 + +
PFB0355c 1401
PFI0135c 3655 2747 3516 +
MAL13P1.310 676 1635 53,119
PF14_0577 1008 2060 +
PF11_0177 781 2058 3604 +
PF11_0298 700 2514 +
PF13_0289 643 1550
PFA0220w 3831 5734 10,100 +
PFD0165w 2208 +
PFD0680c 894 1696 2387 +
PFE1355c 2840 2251 2414 + + +
PFE0835w 2422 1831 +
MAL7P1.147 6182 3575 3628 + + + +
PFI0225w 3780 1998 2117 +
PF13_0096 2105 3554 3789
PF14_0145 1826 2428 +
PFL1635w No oligo + +
MAL8P1.157 2311 2226 1946 +
MAL6P1.153 No oligo + + +
MAL13P1.56 2788 3250 1588 + + + +
PF10_0058 1765 3672 4309
MAL13P1.184 324
PFE1155c 3316 3099 2134 + + +
PFI1625c 2018 4583 4239 + +
PF11_0189 4006 4829 3862 + +
PF11_0226 1002 + + +
PF13_0322 4279 8553 8017 + + + +
PF14_0382 790
PF14_0439 4828 10,517 4692 + + +
PFI1570c 2424 2650 + + + +
PF10_0299 1326 2972 1991 + +
PFE1360c 857 1919 1579 +
MAL8P1.140 3379 2033 +
PF10_0150 2880 2103 + + +
PF14_0327 4130 + + +
PF14_0517 7889 15,722 6630 + + + +
PF11_0203 2440 1695
PFL1925w No oligo +
PF14_0616 5347 1855
MAL8P1.126 1030
PF14_0067 735 +
PFE0370c 3384 5371 +
PF11_0381 1071 2229 10,369 +
PFE0355c 840 4153
PFC0950c No oligo +
PFC0310c 3426 2308 3281
PF14_0348 640 2518 2312
PF08_0063 3901 3233 1715 + + + +
PF14_0063 4125 2130 3154
PF11_0175 8264 2856 4534 + + + +
PF14_0147 1023
PF13_0118 3050 2405 1676
MAL13P1.167 2758 2514 4077
PFE0340c 6507 10,279
MAL8P1.16 No oligo
PF14_0716 8791 9053 6476 + + +
MAL6P1.88 No oligo +
PFC0745c 5944 9387 7742 + +
PF13_0282 7652 7248 5541 + +
PF07_0112 4279 8258 5730 + + + +
MAL8P1.128 No oligo + + +
MAL13P1.270 1487 6809 5159 + + + +
PFE0915c 3396 5939 5761 + +
MAL8P1.142 5571 5814 5579 + + +
PFA0400c No oligo + + + +
PF14_0676 6984 +
PFI1545c No oligo +

a Expression profile of asynchronous culture using Oligo Microarrays. The microarray slide was printed with 6239 70-mers mapped to 4407 predicted open reading frames. Probes were labeled with fluorescent dyes using mRNAs purified from an asynchronous culture as a template (http://derisilab.ucsf.edu/). Briefly, messenger RNAs were purified using oligo T cellulose and reverse transcription was conducted to incorporate aminoallyl dUTP into the cDNAs. The Cy3 and Cy5 NHS esters were then coupled to amine groups of the cDNA, and dye-labeled probes were hybridized with the microarray slides under standard condition (3X SSC, 50% formamide, 0.1% SDS, 10 mg/ml salmon sperm DNA, 68°C). The slide was scanned with a GenePix 4000B (Axon Instrument) at default PMT settings, 100% power. The array data were analyzed initially with GenePixPro software (Axon Instrument), then with global normalization. The expression level is indicated by the mean signal intensity of all corresponding oligomers in triplicates on the microarray slides (MRA-452) obtained from Malaria Research and Reference Resource Center (http://www.malaria.mr4.org/). Ten predicted proteases without corresponding oligomers are highlighted in bold. Two sets of negative controls were included in the DeRisi design: (1) 20 oligomers from yeast intergenic region with the mean intensity 529; (2) 33 P. falciparum genes cloned in the plasmid, including 16 ribosomal proteins, 17 tRNA genes, LSU, Clp, and tufA. Their mean intensity was 598. The percentiles of expression level over all the spots are 297 (30%), 394 (35%), 512 (40%), 646 (45%), and 795 (50%), respectively. The genes that showed signal intensity below the mean of negative controls are highlighted in italic. An asterisk (*) indicates the gene was reported to be expressed in the parasitic life cycle from proteomics data (Florens et al. 2002).

b Expression profile in the erythrocytic stage using cDNA microarray chip containing 944 elements (317 genes of identiable homology; Ben Mamoun et al. 2001). The average intensities were extracted from PlasmoDB. R, ring. A minus sign (–) indicates signal not detected or below the cut-off (35% percentile over all the spots on the array).

c Expression profile in the parasite life cycle using MUDPIT proteomics technology (Florens et al. 2002), extracted from PlasmoDB. A plus sign (+) indicates at least one peptide of the protein was detected by Mass Spectrum. T, trophozoites; M, merozoites; G, gametocytes; S, sporozoites.

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