偽キナーゼとは？わかりやすく解説

偽キナーゼ（ぎキナーゼ、英: Pseudokinases）は、蛋白質キナーゼの触媒能を欠いた偽酵素^[1]変異体であり、生命界のあらゆるキノームに存在する。偽キナーゼは、生理機能（シグナル伝達）と病態生理学的機能の両方を有している^[2]^[3]^[4]^[5]^[6]^[7]。

歴史

偽キナーゼという用語は2002年に初めて造語され^[8]、その後幾つかの「クラス」に細分化された^[9]^[10]^[11]^[12]^[13]。ヒトキノームには、キナーゼとユビキチンE3合成酵素（英語版）シグナル伝達のインターフェースにあるTribbles偽キナーゼなど、幾つかの偽キナーゼ含有ファミリーが存在する^[14]^[15]^[16]。

ヒトの偽キナーゼ（および偽ホスファターゼ類縁蛋白質）は、多様な疾患に関与していることが示唆されており^[17]^[18]、潜在的な薬物標的および抗標的として注目されている^[19]^[20]^[21]^[22]。偽キナーゼは、真核生物の蛋白質キナーゼ（eukaryotic protein kinase; ePK）とePKに関連しない偽酵素蛋白質（例：FAM20A（英語版）; ATPに結合する^[23]、αCヘリックスがグルタミン酸からグルタミンへ変換されて保存された偽キナーゼ）の進化的混合物である^[24]。

FAM20Aは歯周病に関係しており、ゴルジ体で分泌される蛋白質（牛乳蛋白質カゼインなど）のリン酸化を制御する重要な生理学的カゼインキナーゼであるFAM20C（英語版）の触媒活性を制御する役割を果たす^[25]。

包括的な分子進化解析により、偽キナーゼが複数のサブファミリーに分類されることが確認されている。これらのサブファミリーは、原核生物、古細菌、および注釈付きプロテオームを持つすべての真核生物系統を含む、生命界全体にわたる生物の注釈付きキノームに存在する。一部の偽キナーゼはATPの結合能を失っていなかったり、移動した触媒残基に伴う非典型的な反応を触媒したりできる。更に、AlphaFoldなどの構造予測アルゴリズムを使用して偽キナーゼの折り畳みを解析できる^[26]。一部の偽キナーゼは種特異的な適応を示し、例えば脊椎動物の偽キナーゼPSKH2（英語版）は、密接に関連する分泌経路セリン・スレオニンキナーゼPSKH1（英語版）と同様に、ヒト細胞のHsp90 分子シャペロンシステムのクライアントである^[27]。

出典

^ “Bio-Zombie: the rise of pseudoenzymes in biology”. Biochemical Society Transactions 45 (2): 537–544. (April 2017). doi:10.1042/BST20160400. PMID 28408493.
^ “The secret life of kinases: insights into non-catalytic signalling functions from pseudokinases”. Biochemical Society Transactions 45 (3): 665–681. (June 2017). doi:10.1042/BST20160331. PMID 28620028.
^ “A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties”. The Biochemical Journal 457 (2): 323–34. (January 2014). doi:10.1042/BJ20131174. PMC 5679212. PMID 24107129.
^ “Rethinking pseudokinases”. Cell 133 (2): 204–5. (April 2008). doi:10.1016/j.cell.2008.04.005. PMC 6226312. PMID 18423189.
^ “CASK Functions as a Mg2+-independent neurexin kinase”. Cell 133 (2): 328–39. (April 2008). doi:10.1016/j.cell.2008.02.036. PMC 3640377. PMID 18423203.
^ “The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner”. The Biochemical Journal 467 (1): 47–62. (April 2015). doi:10.1042/BJ20141441. PMC 4844368. PMID 25583260.
^ “ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation”. Proceedings of the National Academy of Sciences of the United States of America 107 (17): 7692–7. (April 2010). Bibcode: 2010PNAS..107.7692S. doi:10.1073/pnas.1002753107. PMC 2867849. PMID 20351256.
^ “The protein kinase complement of the human genome”. Science 298 (5600): 1912–34. (December 2002). Bibcode: 2002Sci...298.1912M. doi:10.1126/science.1075762. PMID 12471243.
^ “Emerging roles of pseudokinases”. Trends in Cell Biology 16 (9): 443–52. (September 2006). doi:10.1016/j.tcb.2006.07.003. PMID 16879967.
^ “Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation”. Science 326 (5960): 1707–11. (December 2009). Bibcode: 2009Sci...326.1707Z. doi:10.1126/science.1178377. PMC 3518268. PMID 19892943.
^ “Pseudokinases-remnants of evolution or key allosteric regulators?”. Current Opinion in Structural Biology 20 (6): 772–81. (December 2010). doi:10.1016/j.sbi.2010.10.001. PMC 3014569. PMID 21074407.
^ “Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site”. Structure 17 (1): 128–38. (January 2009). doi:10.1016/j.str.2008.10.018. PMC 2639636. PMID 19141289.
^ “Dawn of the dead: protein pseudokinases signal new adventures in cell biology”. Biochemical Society Transactions 41 (4): 969–74. (August 2013). doi:10.1042/BST20130115. PMID 23863165.
^ “Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease”. Trends in Cell Biology 27 (4): 284–298. (April 2017). doi:10.1016/j.tcb.2016.11.002. PMC 5382568. PMID 27908682.
^ “Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells.”. Science Signaling 11 (549): eaat7951. (September 2018). doi:10.1126/scisignal.aat7951. PMC 6553640. PMID 30254057.
^ “Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1”. Science Signaling 11 (549): eaau0597. (September 2018). doi:10.1126/scisignal.aau0597. PMC 6553639. PMID 30254053.
^ “Day of the dead: pseudokinases and pseudophosphatases in physiology and disease”. Trends in Cell Biology 24 (9): 489–505. (September 2014). doi:10.1016/j.tcb.2014.03.008. PMID 24818526.
^ “Genomics and evolution of protein phosphatases”. Science Signaling 10 (474): eaag1796. (April 2017). doi:10.1126/scisignal.aag1796. PMID 28400531.
^ “Pseudokinases: update on their functions and evaluation as new drug targets”. Future Medicinal Chemistry 9 (2): 245–265. (January 2017). doi:10.4155/fmc-2016-0207. PMID 28097887.
^ “Going for broke: targeting the human cancer pseudokinome”. The Biochemical Journal 465 (2): 195–211. (January 2015). doi:10.1042/BJ20141060. PMID 25559089.
^ “Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases”. Future Medicinal Chemistry 6 (5): 541–61. (April 2014). doi:10.4155/fmc.13.216. PMID 24649957.
^ “Tribbles pseudokinases: novel targets for chemical biology and drug discovery?”. Biochemical Society Transactions 43 (5): 1095–103. (October 2015). doi:10.1042/BST20150109. PMID 26517930.
^ “Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding”. eLife 6. (April 2017). doi:10.7554/eLife.23990. PMC 5413348. PMID 28432788.
^ “A secretory kinase complex regulates extracellular protein phosphorylation”. eLife 4: e06120. (March 2015). doi:10.7554/eLife.06120. PMC 4421793. PMID 25789606.
^ “A Single Kinase Generates the Majority of the Secreted Phosphoproteome”. Cell 161 (7): 1619–32. (June 2015). doi:10.1016/j.cell.2015.05.028. PMC 4963185. PMID 26091039.
^ “Cataloguing the dead: breathing new life into pseudokinase research.”. FEBS J 287 (19): 4150–4169. (Oct 2020). doi:10.1111/febs.15246. PMC 7586955. PMID 32053275.
^ “Evolutionary and cellular analysis of the 'dark' pseudokinase PSKH2”. Biochemical Journal 480 (2): 141–160. (Jan 2023). doi:10.1042/BCJ20220474. PMC 11873932. PMID 39964718.

参考資料

“The evolving world of pseudoenzymes: proteins, prejudice and zombies”. BMC Biology 14 (1). (November 2016). doi:10.1186/s12915-016-0322-x. PMC 5106787. PMID 27835992.

外部リンク

“Professor Patrick Eyers - University of Liverpool Kinome Assay and Screening Facility”. Liverpool.ac.uk. 2017年1月16日閲覧。
“Kinome details and access to KinBase”. 2017年1月16日閲覧。
“Prokino software to analyse kinase site conservation =”. 2017年1月16日閲覧。
“The human pseudokinome wiki”. 2017年1月16日閲覧。

[pmid28408493-1] “Bio-Zombie: the rise of pseudoenzymes in biology”. Biochemical Society Transactions 45 (2): 537–544. (April 2017). doi:10.1042/BST20160400. PMID 28408493.

[pmid28620028-2] “The secret life of kinases: insights into non-catalytic signalling functions from pseudokinases”. Biochemical Society Transactions 45 (3): 665–681. (June 2017). doi:10.1042/BST20160331. PMID 28620028.

[pmid24107129-3] “A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties”. The Biochemical Journal 457 (2): 323–34. (January 2014). doi:10.1042/BJ20131174. PMC 5679212. PMID 24107129.

[pmid18423189-4] “Rethinking pseudokinases”. Cell 133 (2): 204–5. (April 2008). doi:10.1016/j.cell.2008.04.005. PMC 6226312. PMID 18423189.

[pmid18423203-5] “CASK Functions as a Mg2+-independent neurexin kinase”. Cell 133 (2): 328–39. (April 2008). doi:10.1016/j.cell.2008.02.036. PMC 3640377. PMID 18423203.

[pmid25583260-6] “The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner”. The Biochemical Journal 467 (1): 47–62. (April 2015). doi:10.1042/BJ20141441. PMC 4844368. PMID 25583260.

[pmid20351256-7] “ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation”. Proceedings of the National Academy of Sciences of the United States of America 107 (17): 7692–7. (April 2010). Bibcode: 2010PNAS..107.7692S. doi:10.1073/pnas.1002753107. PMC 2867849. PMID 20351256.

[pmid12471243-8] “The protein kinase complement of the human genome”. Science 298 (5600): 1912–34. (December 2002). Bibcode: 2002Sci...298.1912M. doi:10.1126/science.1075762. PMID 12471243.

[pmid16879967-9] “Emerging roles of pseudokinases”. Trends in Cell Biology 16 (9): 443–52. (September 2006). doi:10.1016/j.tcb.2006.07.003. PMID 16879967.

[pmid19892943-10] “Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation”. Science 326 (5960): 1707–11. (December 2009). Bibcode: 2009Sci...326.1707Z. doi:10.1126/science.1178377. PMC 3518268. PMID 19892943.

[pmid21074407-11] “Pseudokinases-remnants of evolution or key allosteric regulators?”. Current Opinion in Structural Biology 20 (6): 772–81. (December 2010). doi:10.1016/j.sbi.2010.10.001. PMC 3014569. PMID 21074407.

[pmid19141289-12] “Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site”. Structure 17 (1): 128–38. (January 2009). doi:10.1016/j.str.2008.10.018. PMC 2639636. PMID 19141289.

[pmid23863165-13] “Dawn of the dead: protein pseudokinases signal new adventures in cell biology”. Biochemical Society Transactions 41 (4): 969–74. (August 2013). doi:10.1042/BST20130115. PMID 23863165.

[pmid27908682-14] “Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease”. Trends in Cell Biology 27 (4): 284–298. (April 2017). doi:10.1016/j.tcb.2016.11.002. PMC 5382568. PMID 27908682.

[pmid30254057-15] “Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells.”. Science Signaling 11 (549): eaat7951. (September 2018). doi:10.1126/scisignal.aat7951. PMC 6553640. PMID 30254057.

[pmid30254053-16] “Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1”. Science Signaling 11 (549): eaau0597. (September 2018). doi:10.1126/scisignal.aau0597. PMC 6553639. PMID 30254053.

[pmid24818526-17] “Day of the dead: pseudokinases and pseudophosphatases in physiology and disease”. Trends in Cell Biology 24 (9): 489–505. (September 2014). doi:10.1016/j.tcb.2014.03.008. PMID 24818526.

[pmid28400531-18] “Genomics and evolution of protein phosphatases”. Science Signaling 10 (474): eaag1796. (April 2017). doi:10.1126/scisignal.aag1796. PMID 28400531.

[pmid28097887-19] “Pseudokinases: update on their functions and evaluation as new drug targets”. Future Medicinal Chemistry 9 (2): 245–265. (January 2017). doi:10.4155/fmc-2016-0207. PMID 28097887.

[pmid25559089-20] “Going for broke: targeting the human cancer pseudokinome”. The Biochemical Journal 465 (2): 195–211. (January 2015). doi:10.1042/BJ20141060. PMID 25559089.

[pmid24649957-21] “Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases”. Future Medicinal Chemistry 6 (5): 541–61. (April 2014). doi:10.4155/fmc.13.216. PMID 24649957.

[pmid26517930-22] “Tribbles pseudokinases: novel targets for chemical biology and drug discovery?”. Biochemical Society Transactions 43 (5): 1095–103. (October 2015). doi:10.1042/BST20150109. PMID 26517930.

[pmid28432788-23] “Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding”. eLife 6. (April 2017). doi:10.7554/eLife.23990. PMC 5413348. PMID 28432788.

[pmid25789606-24] “A secretory kinase complex regulates extracellular protein phosphorylation”. eLife 4: e06120. (March 2015). doi:10.7554/eLife.06120. PMC 4421793. PMID 25789606.

[pmid26091039-25] “A Single Kinase Generates the Majority of the Secreted Phosphoproteome”. Cell 161 (7): 1619–32. (June 2015). doi:10.1016/j.cell.2015.05.028. PMC 4963185. PMID 26091039.

[pmid32053275-26] “Cataloguing the dead: breathing new life into pseudokinase research.”. FEBS J 287 (19): 4150–4169. (Oct 2020). doi:10.1111/febs.15246. PMC 7586955. PMID 32053275.

[pmid36520605-27] “Evolutionary and cellular analysis of the 'dark' pseudokinase PSKH2”. Biochemical Journal 480 (2): 141–160. (Jan 2023). doi:10.1042/BCJ20220474. PMC 11873932. PMID 39964718.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

偽キナーゼとは？わかりやすく解説