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3B7x Lichtarge Lab 2006 Pages 1–5 3b7x Evolutionary trace report by report maker May 28, 2010 4.3.3 DSSP 4 4.3.4 HSSP 4 4.3.5 LaTex 5 4.3.6 Muscle 5 4.3.7 Pymol 5 4.4 Note about ET Viewer 5 4.5 Citing this work 5 4.6 About report maker 5 4.7 Attachments 5 1 INTRODUCTION From the original Protein Data Bank entry (PDB id 3b7x): Title: Crystal structure of human fk506-binding protein 6 Compound: Mol id: 1; molecule: fk506-binding protein 6; chain: a; fragment: ppiase fkbp-type domain: residues 12-144; synonym: peptidyl-prolyl cis-trans isomerase, ppiase, rotamase, 36 kda fk506- binding protein, fkbp-36, immunophilin fkbp36; ec: 5.2.1.8; engi- neered: yes Organism, scientific name: Homo Sapiens; 3b7x contains a single unique chain 3b7xA (117 residues long). CONTENTS 2 CHAIN 3B7XA 2.1 O75344 overview 1 Introduction 1 From SwissProt, id O75344, 93% identical to 3b7xA: 2 Chain 3b7xA 1 Description: FK506-binding protein 6 (EC 5.2.1.8) (Peptidyl-prolyl 2.1 O75344 overview 1 cis-trans isomerase) (PPIase) (Rotamase) (36 kDa FK506 binding 2.2 Multiple sequence alignment for 3b7xA 1 protein) (FKBP- 36) (Immunophilin FKBP36). 2.3 Residue ranking in 3b7xA 1 Organism, scientific name: Homo sapiens (Human). 2.4 Top ranking residues in 3b7xA and their position on Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; the structure 1 Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; 2.4.1 Clustering of residues at 25% coverage. 2 Catarrhini; Hominidae; Homo. 2.4.2 Possible novel functional surfaces at 25% Function: PPIases accelerate the folding of proteins. coverage. 2 Catalytic activity: Peptidylproline (omega=180) = peptidylproline (omega=0). 3 Notes on using trace results 3 Tissue specificity: Detected in all tissues examined, with higher 3.1 Coverage 3 expression in testis, heart, skeletal muscle, liver, and kidney. 3.2 Known substitutions 3 Disease: Haploinsufficiency of FKBP6 may be the cause of cer- 3.3 Surface 3 tain cardiovascular and musculo-skeletal abnormalities observed in 3.4 Number of contacts 3 Williams-Beuren syndrome (WBS) [MIM:194050]; a rare develop- 3.5 Annotation 4 mental disorder. It is a contiguous gene deletion syndrome involving 3.6 Mutation suggestions 4 genes from chromosome band 7q11.23. Similarity: Contains 1 PPIase FKBP-type domain. 4 Appendix 4 Similarity: Contains 3 TPR repeats. 4.1 File formats 4 About: This Swiss-Prot entry is copyright. It is produced through a 4.2 Color schemes used 4 collaboration between the Swiss Institute of Bioinformatics and the 4.3 Credits 4 EMBL outstation - the European Bioinformatics Institute. There are 4.3.1 Alistat 4 no restrictions on its use as long as its content is in no way modified 4.3.2 CE 4 and this statement is not removed. 1 Lichtarge lab 2006 Fig. 1. Residues 19-143 in 3b7xA colored by their relative importance. (See Appendix, Fig.5, for the coloring scheme.) 2.2 Multiple sequence alignment for 3b7xA For the chain 3b7xA, the alignment 3b7xA.msf (attached) with 41 sequences was used. The alignment was downloaded from the HSSP database, and fragments shorter than 75% of the query as well as duplicate sequences were removed. It can be found in the attachment to this report, under the name of 3b7xA.msf. Its statistics, from the alistat program are the following: Format: MSF Number of sequences: 41 Total number of residues: 4182 Fig. 2. Residues in 3b7xA, colored by their relative importance. Clockwise: front, back, top and bottom views. Smallest: 88 Largest: 117 Average length: 102.0 Alignment length: 117 Average identity: 46% Most related pair: 99% Most unrelated pair: 20% Most distant seq: 49% Furthermore, 4% of residues show as conserved in this alignment. The alignment consists of 63% eukaryotic ( 41% vertebrata, 7% arthropoda, 7% plantae) sequences. (Descriptions of some sequences were not readily available.) The file containing the sequence descrip- tions can be found in the attachment, under the name 3b7xA.descr. 2.3 Residue ranking in 3b7xA The 3b7xA sequence is shown in Fig. 1, with each residue colored according to its estimated importance. The full listing of residues in 3b7xA can be found in the file called 3b7xA.ranks sorted in the attachment. 2.4 Top ranking residues in 3b7xA and their position on the structure In the following we consider residues ranking among top 25% of Fig. 3. Residues in 3b7xA, colored according to the cluster they belong to: residues in the protein . Figure 2 shows residues in 3b7xA colored red, followed by blue and yellow are the largest clusters (see Appendix for by their importance: bright red and yellow indicate more conser- the coloring scheme). Clockwise: front, back, top and bottom views. The ved/important residues (see Appendix for the coloring scheme). A corresponding Pymol script is attached. Pymol script for producing this figure can be found in the attachment. Table 1. 2.4.1 Clustering of residues at 25% coverage. Fig. 3 shows the cluster size member top 25% of all residues, this time colored according to clusters they color residues belong to. The clusters in Fig.3 are composed of the residues listed continued in next column in Table 1. 2 Table 1. continued Table 2. continued cluster size member res type substitutions(%) cvg color residues 35 D D(92)N(4).(2) 0.15 red 28 35,40,46,61,63,72,94,98,102 125 P P(90)S(2)N(2) 0.16 105,106,108,110,112,114,116 D(2)Q(2) 117,118,119,122,125,127,128 135 F F(90)W(2)Y(7) 0.17 129,132,135,136,138 138 E E(90)Q(2)H(2) 0.19 .(2)K(2) Table 1. Clusters of top ranking residues in 3b7xA. 119 G G(92)K(2)R(2) 0.20 H(2) 129 P P(70)G(4)S(21) 0.21 2.4.2 Possible novel functional surfaces at 25% coverage. One A(2) group of residues is conserved on the 3b7xA surface, away from (or 72 F F(85)Y(4).(7) 0.23 susbtantially larger than) other functional sites and interfaces reco- S(2) gnizable in PDB entry 3b7x. It is shown in Fig. 4. The right panel 136 E E(78)K(9)D(9) 0.25 shows (in blue) the rest of the larger cluster this surface belongs to. I(2) Table 2. Residues forming surface ”patch” in 3b7xA. Table 3. res type disruptive mutations 40 K (Y)(FTW)(SVCAG)(HD) 106 E (FWH)(YVCARG)(T)(SNKLPI) 122 G (KER)(FQMWHD)(NYLPI)(SVA) 128 P (Y)(T)(HR)(SCG) 127 I (YR)(H)(TKE)(SQCDG) 118 Y (K)(Q)(EM)(NR) Fig. 4. A possible active surface on the chain 3b7xA. The larger cluster it 46 G (KR)(E)(QH)(FMW) belongs to is shown in blue. 114 P (R)(Y)(H)(T) 105 G (K)(R)(E)(QM) 116 Y (K)(R)(Q)(E) The residues belonging to this surface ”patch” are listed in Table 117 A (R)(KYE)(H)(QD) 2, while Table 3 suggests possible disruptive replacements for these 61 Y (K)(Q)(M)(NER) residues (see Section 3.6). 132 T (R)(K)(H)(FW) Table 2. 35 D (R)(FWH)(YVCAG)(T) res type substitutions(%) cvg 125 P (Y)(R)(H)(T) 40 K K(100) 0.04 135 F (K)(E)(Q)(D) 106 E E(100) 0.04 138 E (FW)(YVAH)(CG)(T) 122 G G(100) 0.04 119 G (E)(D)(FMW)(KY) 128 P P(90)K(9) 0.05 129 P (R)(Y)(H)(K) 127 I I(97)V(2) 0.06 72 F (K)(E)(Q)(D) 118 Y Y(87)F(12) 0.07 136 E (FWH)(Y)(CRG)(VA) 46 G A(7)G(90)S(2) 0.08 114 P P(85)K(2)Y(9) 0.09 Table 3. Disruptive mutations for the surface patch in 3b7xA. S(2) 105 G G(90)Y(7)S(2) 0.10 116 Y Y(82)L(14)V(2) 0.11 117 A A(80)V(2)L(9) 0.12 3 NOTES ON USING TRACE RESULTS G(7) 3.1 Coverage 61 Y Y(92)S(2)F(2) 0.14 .(2) Trace results are commonly expressed in terms of coverage: the resi- 132 T T(80)D(9)E(2) 0.14 due is important if its “coverage” is small - that is if it belongs to A(2)V(4) some small top percentage of residues [100% is all of the residues continued in next column in a chain], according to trace. The ET results are presented in the form of a table, usually limited to top 25% percent of residues (or to some nearby percentage), sorted by the strength of the presumed evolutionary pressure. (I.e., the smaller the coverage, the stronger the 3 pressure on the residue.) Starting from the top of that list, mutating a couple of residues should affect the protein somehow, with the exact effects to be determined experimentally. 3.2 Known substitutions COVERAGE One of the table columns is “substitutions” - other amino acid types seen at the same position in the alignment. These amino acid types V may be interchangeable at that position in the protein, so if one wants 100% 50% 30% 5% to affect the protein by a point mutation, they should be avoided. For example if the substitutions are “RVK” and the original protein has an R at that position, it is advisable to try anything, but RVK.
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