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Walker motifs
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<h2 id="walker-a-motif">Walker A motif</h2> <p>Walker A motif, also known as the Walker loop, or P-loop, or phosphate-binding loop, is a motif in <a href="/facts/Proteins/Jxmagu3E">proteins</a> that is associated with <a href="/facts/Phosphate/FDGVCxUG">phosphate</a> binding. The motif has the pattern G-x(4)-GK-[TS], where G, K, T and S denote <a href="/facts/Glycine/3nXI1hqW">glycine</a>, <a href="/facts/Lysine/CEetgA9L">lysine</a>, <a href="/facts/Threonine/7zffFQ6W">threonine</a> and <a href="/facts/Serine/4duVl30B">serine</a> residues respectively, and x denotes any <a href="/facts/Amino_acid/WDxYwBny">amino acid</a>. It is present in many <a href="/facts/Adenosine_triphosphate/nB9bwgcU">ATP</a> or <a href="/facts/Guanosine_triphosphate/NAwoHjTW">GTP</a> utilizing proteins; it is the β phosphate of the <a href="/facts/Nucleotide/pQKEwlJI">nucleotide</a> that is bound. The <a href="/facts/Lysine/CEetgA9L">lysine</a> (K) residue in the Walker A motif, together with the main chain NH atoms, are crucial for <a href="/facts/Nucleotide/pQKEwlJI">nucleotide</a>-binding.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> It is a <a href="/facts/Glycine/3nXI1hqW">glycine</a>-rich loop preceded by a <a href="/facts/Beta_strand/B6mwwR6H">beta strand</a> and followed by an <a href="/facts/Alpha_helix/7CESPIYJ">alpha helix</a>; these features are typically part of an α/β domain with four strands sandwiched between two helices on each side. The <a href="/facts/Phosphate_group/FDGVCxUG">phosphate groups</a> of the <a href="/facts/Nucleotide/pQKEwlJI">nucleotide</a> are also coordinated to a divalent cation such as a <a href="/facts/Magnesium/XyIhd2FG">magnesium</a>, <a href="/facts/Calcium/hf252CC0">calcium</a>, or <a href="/facts/Manganese/j9ELd1TL">manganese</a>(II) ion.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>Apart from the conserved lysine, a feature of the P-loop used in phosphate binding is a compound LRLR <a href="/facts/Nest_(protein_structural_motif)/hjckhbHu">nest</a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> comprising the four residues xxGK, as above, whose main chain atoms form a phosphate-sized concavity with the NH groups pointing inwards. The synthetic hexapeptide SGAGKT has been shown<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> to bind inorganic phosphate strongly; since such a short peptide does not form an <a href="/facts/Alpha_helix/7CESPIYJ">alpha helix</a>, this suggests that it is the nest, rather than being at the <a href="/facts/N-terminus/yKYpuaBJ">N-terminus</a> of a helix, that is the main phosphate binding feature. </p><p>Upon nucleotide hydrolysis the loop does not significantly change the protein <a href="/facts/Conformational_change/q23CgKgo">conformation</a>, but stays bound to the remaining phosphate groups. Walker motif A-binding has been shown to cause structural changes in the bound nucleotide, along the line of the <a href="/facts/Induced_fit_model/DSI1Fh7y">induced fit model</a> of <a href="/facts/Enzyme/DSI1Fh7y">enzyme</a> binding. </p> <h3>Similar folds</h3> <p>PTPs (<a href="/facts/Protein_tyrosine_phosphatase/5mEgPxAw">protein tyrosine phosphatases</a>) that catalyse the hydrolysis of an inorganic phosphate from a <a href="/facts/Phosphotyrosine/RJhEgE4C">phosphotyrosine</a> residue (the reverse of a <a href="/facts/Tyrosine_kinase/26Ln0qJ4">tyrosine kinase</a> reaction) contain a motif which folds into a P-loop-like structure with an arginine in the place of the conserved lysine. The conserved sequence of this motif is C-x(5)-R-[ST], where C and R denote <a href="/facts/Cysteine/kbqvUm6d">cysteine</a> and <a href="/facts/Arginine/y49Hdf1e">arginine</a> residues respectively.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p><p><a href="/facts/Pyridoxal_phosphate/GTGIzISg">Pyridoxal phosphate</a> (PLP) utilizing enzymes such as <a href="/facts/Cysteine_synthase/dSrkaDnC">cysteine synthase</a> have also been said to resemble a P-loop. </p> <h3>A-loop</h3> <p>The A-loop (<a href="/facts/Aromaticity/wK0DzRY6">aromatic</a> residue interacting with the <a href="/facts/Adenine/PSeDFBnl">adenine</a> ring of ATP) refers to conserved <a href="/facts/Aromatic_amino_acid/lkh9b0Ax">aromatic amino acids</a>, essential for ATP-binding, found in about 25 amino acids upstream of the Walker A motif in a subset of P-loop proteins.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h2 id="walker-b-motif">Walker B motif</h2> <p>Walker B motif is a <a href="/facts/Structural_motif/g8EBDBGW">motif</a> in most P-loop proteins situated well downstream of the A-motif. The consensus sequence of this motif was reported to be [RK]-x(3)-G-x(3)-LhhhD, where R, K, G, L and D denote <a href="/facts/Arginine/y49Hdf1e">arginine</a>, <a href="/facts/Lysine/CEetgA9L">lysine</a>, <a href="/facts/Glycine/3nXI1hqW">glycine</a>, <a href="/facts/Leucine/X7YrkvA5">leucine</a> and <a href="/facts/Aspartic_acid/9DFSFPa1">aspartic acid</a> residues respectively, x represents any of the 20 standard amino acids and h denotes a <a href="/facts/Hydrophobic/Ifya0CXQ">hydrophobic</a> amino acid.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> This motif was changed to be hhhhDE, where E denotes a <a href="/facts/Glutamate/7oXbNcvu">glutamate</a> residue.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> The <a href="/facts/Aspartate/9DFSFPa1">aspartate</a> and glutamate also form a part of the <a href="/facts/DEAD_box/Io5dNsC6">DEAD/DEAH</a> motifs found in <a href="/facts/Helicase/IemubWzR">helicases</a>. The aspartate residue co-ordinates magnesium ions, and the glutamate is essential for <a href="/facts/ATP_hydrolysis/940XnJMX">ATP hydrolysis</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> There is considerable variability in the sequence of this motif, with the only invariant features being a negatively charged residue following a stretch of bulky, hydrophobic amino acids.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p> <h2 id="evolutionary-connections">Evolutionary connections</h2> <p>There is a hypothesis that the Walker A phosphate binding motif can be evolutionarily related to <a href="/facts/Rossmann_fold/dqcN0HSa">Rossman</a>'s fold phosphate binding motif because of the shared principles in the location of the binding loop between the first β-strand and α-helix in the αβα sandwich fold and positioning of the functionally important aspartate on the tip of the second β-strand.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Activation_loop/KrnRkv7K">Activation loop</a></li> <li><a href="/facts/Autophosphorylation/2fxju7UD">Autophosphorylation</a></li> <li><a href="/facts/Ca2%252B%2fcalmodulin-dependent_protein_kinase/P8xWo0vB">Ca2+/calmodulin-dependent protein kinase</a></li> <li><a href="/facts/Cell_signaling/6oYAVP9I">Cell signaling</a></li> <li><a href="/facts/Cyclin-dependent_kinase/ppYkzTaR">Cyclin-dependent kinase</a></li> <li><a href="/facts/G_protein-coupled_receptor/0arUMkQc">G protein-coupled receptor</a></li> <li><a href="/facts/Nucleoside-diphosphate_kinase/t0P4JXLv">Nucleoside-diphosphate kinase</a></li> <li><a href="/facts/Phosphatase/LBJs1fXx">Phosphatase</a></li> <li><a href="/facts/Phosphatidylinositol_phosphate_kinases/5xnKuXFE">Phosphatidylinositol phosphate kinases</a></li> <li><a href="/facts/Phospholipid/u6GhNCF5">Phospholipid</a></li> <li><a href="/facts/Phosphoprotein/oTx9DWbU">Phosphoprotein</a></li> <li><a href="/facts/Phosphorylation/LXUEEeIL">Phosphorylation</a></li> <li><a href="/facts/Phosphotransferase/pGqKzt3D">Phosphotransferase</a></li> <li><a href="/facts/Signal_transduction/1bs0Me6w">Signal transduction</a></li> <li><a href="/facts/Thymidine_kinase/uX8MoG90">Thymidine kinase</a></li> <li><a href="/facts/Thymidine_kinase_in_clinical_chemistry/jRXM15F3">Thymidine kinase in clinical chemistry</a></li> <li><a href="/facts/Thymidylate_kinase/vXfLXSd2">Thymidylate kinase</a></li> <li><a href="/facts/Wall-associated_kinase/UqFcyL4E">Wall-associated kinase</a></li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="http://expasy.org/cgi-bin/get-prodoc-entry?PDOC00017">Prosite entry for Walker A motif, PS00017</a></li> <li><a href="http://expasy.org/prosite/PDOC51195">Prosite entry for DEAD box motif PS51195</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Walker JE, Saraste M, Runswick MJ, Gay NJ (1982). "Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold". The EMBO Journal. 1 (8): 945–951. doi:10.1002/j.1460-2075.1982.tb01276.x. PMC 553140. PMID 6329717. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC553140" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC553140</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Leipe DD, Wolf YI, Koonin EV, Aravind L (March 2002). "Classification and evolution of P-loop GTPases and related ATPases". Journal of Molecular Biology. 317 (1): 41–72. doi:10.1006/jmbi.2001.5378. PMID 11916378. <a href="https://zenodo.org/record/1229904" target="_blank">https://zenodo.org/record/1229904</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Stryer L, Berg JM, Tymoczko JL (2002). Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4684-0. <a href="0-7167-4684-0" target="_blank">0-7167-4684-0</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Ramakrishnan C, Dani VS, Ramasarma T (October 2002). "A conformational analysis of Walker motif A [GXXXXGKT (S)] in nucleotide-binding and other proteins". Protein Engineering. 15 (10): 783–798. doi:10.1093/protein/15.10.783. PMID 12468712. <a href="https://doi.org/10.1093%2Fprotein%2F15.10.783" target="_blank">https://doi.org/10.1093%2Fprotein%2F15.10.783</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Saraste M, Sibbald PR, Wittinghofer A (November 1990). "The P-loop--a common motif in ATP- and GTP-binding proteins". Trends in Biochemical Sciences. 15 (11): 430–434. doi:10.1016/0968-0004(90)90281-f. PMID 2126155. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Hanson PI, Whiteheart SW (July 2005). "AAA+ proteins: have engine, will work". Nature Reviews. Molecular Cell Biology. 6 (7): 519–529. doi:10.1038/nrm1684. PMID 16072036. S2CID 27830342. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Bugreev DV, Mazin AV (July 2004). "Ca2+ activates human homologous recombination protein Rad51 by modulating its ATPase activity". Proceedings of the National Academy of Sciences of the United States of America. 101 (27): 9988–9993. Bibcode:2004PNAS..101.9988B. doi:10.1073/pnas.0402105101. PMC 454202. PMID 15226506. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC454202" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC454202</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Watson JD, Milner-White EJ (January 2002). "A novel main-chain anion-binding site in proteins: the nest. A particular combination of phi,psi values in successive residues gives rise to anion-binding sites that occur commonly and are found often at functionally important regions". Journal of Molecular Biology. 315 (2): 171–182. doi:10.1006/jmbi.2001.5227. PMID 11779237. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Bianchi A, Giorgi C, Ruzza P, Toniolo C, Milner-White EJ (May 2012). "A synthetic hexapeptide designed to resemble a proteinaceous P-loop nest is shown to bind inorganic phosphate". Proteins. 80 (5): 1418–1424. doi:10.1002/prot.24038. PMID 22275093. S2CID 5401588. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Zhang M, Stauffacher CV, Lin D, Van Etten RL (August 1998). "Crystal structure of a human low molecular weight phosphotyrosyl phosphatase. Implications for substrate specificity". The Journal of Biological Chemistry. 273 (34): 21714–21720. doi:10.1074/jbc.273.34.21714. PMID 9705307. <a href="https://doi.org/10.1074%2Fjbc.273.34.21714" target="_blank">https://doi.org/10.1074%2Fjbc.273.34.21714</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Ambudkar SV, Kim IW, Xia D, Sauna ZE (February 2006). "The A-loop, a novel conserved aromatic acid subdomain upstream of the Walker A motif in ABC transporters, is critical for ATP binding". FEBS Letters. 580 (4): 1049–1055. doi:10.1016/j.febslet.2005.12.051. PMID 16412422. <a href="https://doi.org/10.1016%2Fj.febslet.2005.12.051" target="_blank">https://doi.org/10.1016%2Fj.febslet.2005.12.051</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Walker JE, Saraste M, Runswick MJ, Gay NJ (1982). "Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold". The EMBO Journal. 1 (8): 945–951. doi:10.1002/j.1460-2075.1982.tb01276.x. PMC 553140. PMID 6329717. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC553140" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC553140</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Hanson PI, Whiteheart SW (July 2005). "AAA+ proteins: have engine, will work". Nature Reviews. Molecular Cell Biology. 6 (7): 519–529. doi:10.1038/nrm1684. PMID 16072036. S2CID 27830342. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Hanson PI, Whiteheart SW (July 2005). "AAA+ proteins: have engine, will work". Nature Reviews. Molecular Cell Biology. 6 (7): 519–529. doi:10.1038/nrm1684. PMID 16072036. S2CID 27830342. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Koonin EV (June 1993). "A common set of conserved motifs in a vast variety of putative nucleic acid-dependent ATPases including MCM proteins involved in the initiation of eukaryotic DNA replication". Nucleic Acids Research. 21 (11): 2541–2547. doi:10.1093/nar/21.11.2541. PMC 309579. PMID 8332451. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC309579" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC309579</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Longo LM, Jabłońska J, Vyas P, Kanade M, Kolodny R, Ben-Tal N, Tawfik DS (December 2020). Deane CM, Boudker O (eds.). "On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment". eLife. 9: e64415. doi:10.7554/eLife.64415. PMC 7758060. PMID 33295875. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758060" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758060</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> </ol>