Proteína quinase activada por mitóxeno: Diferenzas entre revisións
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Liña 74:
A separación entre as MAP quinases clásicas e atípicas ocorreu bastante cedo. Isto é suxerido non simplemente pola diverxencia entre os xéneros existentes, pero tamén os descubrimentos recentes de MAPK atípicas en eucariotas basais primitivos. A secuenciación do [[xenoma]] de ''[[Giardia lamblia]]'' revelou a presenza de dous xenes MAPK, un deles similar ´s ben coñecidas MAPK de mmíferos (ERKs, p38s etc.), e a outra mostraba semellanzas coa proteína ERK7 de mamíferos.<ref name="pmid12397063">{{cite journal | vauthors = Ellis JG, Davila M, Chakrabarti R | title = Potential involvement of extracellular signal-regulated kinase 1 and 2 in encystation of a primitive eukaryote, Giardia lamblia. Stage-specific activation and intracellular localization | journal = The Journal of Biological Chemistry | volume = 278 | issue = 3 | pages = 1936–45 | date = Jan 2003 | pmid = 12397063 | doi = 10.1074/jbc.M209274200 }}</ref> A situación é siilar no organismo [[ameboide]] multicelular ''[[Dictyostelium discoideum]]'', no que a proteína ddERK1 paree ser unha MAPK clásica, mentres que ddERK2 lembra máis ás proteínas ERK7 e ERK3/4 de mamíferos.<ref name="pmid21666837">{{cite journal | vauthors = Hadwiger JA, Nguyen HN | title = MAPKs in development: insights from Dictyostelium signaling pathways | journal = Biomolecular Concepts | volume = 2 | issue = 1–2 | pages = 39–46 | date = Apr 2011 | pmid = 21666837 | pmc = 3110071 | doi = 10.1515/BMC.2011.004 }}</ref> As MAPK atípicas poden tamén encontrarse en plantas superiores, aínda que se sabe pouco delas. Igual que ocorre en mamíferos, a maioría dos aspectos das MAPK atípicas non están cataterizados debido á falta de investigación nese campo.
== Recoñecemento
[[Ficheiro:D-motif-overview.png|miniatura|Diagrama das interaccións das MAPK dependentes do motivo D e o recolecemento de substrato.<ref name="pmid23047924">{{cite journal | vauthors = Garai Á, Zeke A, Gógl G, Törő I, Fördős F, Blankenburg H, Bárkai T, Varga J, Alexa A, Emig D, Albrecht M, Reményi A | title = Specificity of linear motifs that bind to a common mitogen-activated protein kinase docking groove | journal = Science Signaling | volume = 5 | issue = 245 | pages = ra74 | date = Oct 2012 | pmid = 23047924 | pmc = 3500698 | doi = 10.1126/scisignal.2003004 }}</ref> Todos os exemplos citados refírense ás interaccións da proteína de mamíferos ERK2.]]
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As typical for the CMGC kinase group, the catalytic site of MAP kinases has a very loose consensus sequence for [[Enzyme substrate (biology)|substrates]]. Like all their relatives, they only require the target [[serine]] / [[threonine]] amino acids to be followed by a small amino acid, preferably [[proline]] ("proline-directed kinases"). But as SP/TP sites are extremely common in all proteins, additional substrate-recognition mechanisms have evolved to ensure signaling fidelty.<ref name="pmid23047924"/> Unlike their closest relatives, the [[cyclin-dependent kinases]] (CDKs), where substrates are recognized by the [[cyclin]] subunit, MAPKs associate with their substrates via auxiliary binding regions on their kinase domains. The most important such region consists of the hydrophobic docking groove and the negatively charged CD-region. Together they recognize the so-called MAPK docking or D-motifs (also called kinase interaction motif / KIM). D-motifs essentially consist of one or two positively charged amino acids, followed by alternating hydrophobic residues (mostly leucines), typically upstream of the phosphorylation site by 10–50 amino acids.<ref name="pmid16364919">{{cite journal | vauthors = Reményi A, Good MC, Bhattacharyya RP, Lim WA | title = The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network | journal = Molecular Cell | volume = 20 | issue = 6 | pages = 951–62 | date = Dec 2005 | pmid = 16364919 | doi = 10.1016/j.molcel.2005.10.030 }}</ref> Many of the known MAPK substrates contain such D-motifs that can not only bind to, but also provide specific recognition by certain MAPKs. Interestingly, D-motifs are not restricted to substrates: MAP2 kinases also contain such motifs on their [[N-terminus|N-termini]] that are absolutely required for MAP2K-MAPK interaction and MAPK activation.<ref name="pmid19196711">{{cite journal | vauthors = Bardwell AJ, Frankson E, Bardwell L | title = Selectivity of docking sites in MAPK kinases | journal = The Journal of Biological Chemistry | volume = 284 | issue = 19 | pages = 13165–73 | date = May 2009 | pmid = 19196711 | pmc = 2676048 | doi = 10.1074/jbc.M900080200 }}</ref> Similarly, both dual-specificity MAP kinase phosphatases and MAP-specific tyrosine phosphatases bind to MAP kinases through the same docking site.<ref name="pmid22375047">{{cite journal | vauthors = Goldsmith EJ | title = Three-dimensional docking in the MAPK p38α | journal = Science Signaling | volume = 4 | issue = 204 | pages = pe47 | date = Dec 2011 | pmid = 22375047 | doi = 10.1126/scisignal.2002697 }}</ref><ref name="pmid15466470">{{cite journal | vauthors = Huang Z, Zhou B, Zhang ZY | title = Molecular determinants of substrate recognition in hematopoietic protein-tyrosine phosphatase | journal = The Journal of Biological Chemistry | volume = 279 | issue = 50 | pages = 52150–9 | date = Dec 2004 | pmid = 15466470 | doi = 10.1074/jbc.M407820200 }}</ref> D-motifs can even be found in certain MAPK pathway regulators and scaffolds (e.g. in the mammalian JIP proteins).▼
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Existen outros sitios de unión ao substrato peor coñecidos. Un deses sitios (o sitio DEF) está formado polo bucle de activación (cando está na conformación activa) e a MAP quinase-específica inserida baixo el. Este sitio pode acomodar [[péptido]]s cunha secuencia consenso FxFP, normalmente situada augas abaixo do sitio de fosforilación.<ref name="pmid18482985">{{cite journal | vauthors = Sheridan DL, Kong Y, Parker SA, Dalby KN, Turk BE | title = Substrate discrimination among mitogen-activated protein kinases through distinct docking sequence motifs | journal = The Journal of Biological Chemistry | volume = 283 | issue = 28 | pages = 19511–20 | date = Jul 2008 | pmid = 18482985 | pmc = 2443660 | doi = 10.1074/jbc.M801074200 }}</ref> Nótese que dito sitio só pode encontrarse en proteínas que necesitan recoñecer selectivamente as MAP quinases activas, así encóntranse case exclusivamente en substratos. Diferentes motivos poden cooperar entre si, como ocorre na familia Elk de factores de transcrición, que posúen tanto o motivo D coma o FxFP. A presenza dun motivo FxFP na proteína armazón KSR1 tamén serve para facer dela un substrato de ERK1/2, proporcionando un mecanismo de retroalimentación negativa para establecer a forza correcta de activación de ERK1/2.
== Proteínas armazón ==▼
▲== Proteínas armazón ==
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Since the discovery of Ste5 in yeast, scientists were on the hunt to discover similar non-enzymatic scaffolding pathway elements in mammals. There are indeed a number of proteins involved in ERK signaling, that can bind to multiple elements of the pathway: [[MAP2K1IP1|MP1]] binds both MKK1/2 and ERK1/2, [[KSR1]] and [[KSR2]] can bind B-Raf or c-Raf, MKK1/2 and ERK1/2. Analogous proteins were also discovered for the JNK pathway: the [[MAPK8IP1|JIP1]]/[[MAPK8IP2|JIP2]] and the [[MAPK8IP3|JIP3]]/[[MAPK8IP4|JIP4]] families of proteins were all shown to bind MLKs, MKK7 and any JNK kinase. Unfortunately, unlike the yeast Ste5, the mechanisms by which they regulate MAPK activation are considerably less understood. While Ste5 actually forms a ternary complex with Ste7 and Fus3 to promote phosphorylation of the latter, known mammalian scaffold proteins appear to work by very different mechanisms. For example, KSR1 and KSR2 are actually MAP3 kinases and related to the Raf proteins.<ref name="pmid22292131">{{cite journal | vauthors = McKay MM, Freeman AK, Morrison DK | title = Complexity in KSR function revealed by Raf inhibitor and KSR structure studies | journal = Small GTPases | volume = 2 | issue = 5 | pages = 276–281 | date = Sep 2011 | pmid = 22292131 | pmc = 3265819 | doi = 10.4161/sgtp.2.5.17740 }}</ref> Although KSRs alone display negligible MAP3 kinase activity, KSR proteins can still participate in the activation of Raf kinases by forming side-to-side heterodimers with them, providing an allosteric pair to turn on each enzymes.<ref name="pmid21441910">{{cite journal | vauthors = Brennan DF, Dar AC, Hertz NT, Chao WC, Burlingame AL, Shokat KM, Barford D | title = A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK | journal = Nature | volume = 472 | issue = 7343 | pages = 366–9 | date = Apr 2011 | pmid = 21441910 | doi = 10.1038/nature09860 }}</ref> JIPs on the other hand, are apparently transport proteins, responsible for enrichment of MAPK signaling components in certain compartments of polarized cells.<ref name="pmid18081006">{{cite journal | vauthors = Koushika SP | title = "JIP"ing along the axon: the complex roles of JIPs in axonal transport | journal = BioEssays | volume = 30 | issue = 1 | pages = 10–4 | date = Jan 2008 | pmid = 18081006 | doi = 10.1002/bies.20695 }}</ref> In this context, JNK-dependent phosphorylation of JIP1 (and possibly JIP2) provides a signal for JIPs to release the JIP-bound and inactive upstream pathway components, thus driving a strong local positive feedback loop.<ref name="pmid12756254">{{cite journal | vauthors = Nihalani D, Wong HN, Holzman LB | title = Recruitment of JNK to JIP1 and JNK-dependent JIP1 phosphorylation regulates JNK module dynamics and activation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 31 | pages = 28694–702 | date = Aug 2003 | pmid = 12756254 | doi = 10.1074/jbc.M304212200 }}</ref> This sophisticated mechanism couples [[kinesin|kinesin-dependent transport]] to local JNK activation, not only in mammals, but also in the fruitfly ''[[Drosophila melanogaster]]''.<ref name="pmid17658258">{{cite journal | vauthors = Horiuchi D, Collins CA, Bhat P, Barkus RV, Diantonio A, Saxton WM | title = Control of a kinesin-cargo linkage mechanism by JNK pathway kinases | journal = Current Biology | volume = 17 | issue = 15 | pages = 1313–7 | date = Aug 2007 | pmid = 17658258 | pmc = 2041807 | doi = 10.1016/j.cub.2007.06.062 }}</ref>
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