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Effects of T208E activating mutation on MARK2 protein structure and dynamics: Modeling and simulation | ||
| Molecular Biology Research Communications | ||
| مقاله 1، دوره 3، شماره 3، آذر 2014، صفحه 149-164 اصل مقاله (1.35 M) | ||
| نوع مقاله: Original article | ||
| شناسه دیجیتال (DOI): 10.22099/mbrc.2014.2195 | ||
| نویسندگان | ||
| Sajjad Ahrari؛ Navid Mogharrab* | ||
| Department of Biology, College of Sciences, Shiraz University | ||
| چکیده | ||
| Microtubule Affinity-Regulating Kinase 2 (MARK2) protein has a substantial role in regulation of vital cellular processes like induction of polarity, regulation of cell junctions, cytoskeleton structure and cell differentiation. The abnormal function of this protein has been associated with a number of pathological conditions like Alzheimer disease, autism, several carcinomas and development of virulent effects of Helicobacter pylori. Here we tried to verify the structural changes induced in MARK2 by T208E activating mutation using molecular modeling and molecular dynamics simulation. Our results show that the enzyme structure shifts toward the active state due to T208E mutation, but this process is not a uniform change in all through the expected regions. Within the N-lobe of the protein, those functional regions having little or no interaction with the UBA domain, like N-half of b2, b4 strands and aC-helix, go through activating motions and those having close interactions with UBA domain like C-half of b1, b3 and b5 strands are comparatively held in-place and don’t accompany. Within the C-lobe, only activation segment has noticeable displacements. Free energy calculations also indicate higher affinity of UBA domain for protein N-lobe in mutant structure (∆∆G = -9 kJ/mol) which is suggestive of a more intimate interaction between the UBA domain and protein N-lobe in mutant structure. | ||
| کلیدواژه‌ها | ||
| MARK2؛ Kinase protein regulation؛ UBA domain؛ Auto-inhibition؛ Molecular dynamics simulation؛ Molecular modeling | ||
| اصل مقاله | ||
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MARKII, Kinase protein regulation, UBA domain, Auto-inhibition, Structural dynamics | ||
| مراجع | ||
|
1.Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002;298:1912-1934.
2.Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 1997;89:297-308.
3.Guo S, Kemphues KJ. Par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 1995;81:611-620.
4.Espinosa L, Navarro E. Human serine/threonine protein kinase EMK1: genomic structure and cDNA cloning of isoforms produced by alternative splicing. Cytogenet Genome Res 1998;81:278-282.
5.Böhm H, Brinkmann V, Drab M, Henske A, Kurzchalia TV. Mammalian homologues of C. elegans PAR-1 are asymmetrically localized in epithelial cells and may influence their polarity. Curr Biol 1997;7:603-606.
6.Zhang X, Zhu J, Yang GY, Wang QL, Qian L, Chen YM, Chen F, Tao T, Hu HS, Wang T, Luo ZG. Dishevelled promotes axon differentiation by regulating atypical protein kinase C. Nat Cell Biol 2007;9:743-754.
7.Cohen D, Brennwald PJ, Rodriguez-Boulan E, Müsch A. Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. J Cell Biol 2004;164:717-727.
8.Cohen D, Rodriguez-Boulan E, Müsch A. Par-1 promotes a hepatic mode of apical protein trafficking in MDCK cells. Proc Nati Acad Sci USA 2004;101: 13792–13797.
9.Matenia D, Mandelkow EM. The tau of MARK: a polarized view of the cytoskeleton. Trends Biochem Sci 2009;34:332-342
10.Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Mäkelä TP, Hardie DG, Alessi DR. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 2004;23: 833-843.
11.Timm T, Li XY, Biernat J, Jiao J, Mandelkow E, Vandekerckhove J, Mandelkow EM. MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1. EMBO J 2003;22:5090-5101.
12.Marx A, Nugoor C, Panneerselvam S, Mandelkow E. Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases. FASEB J 2010;24;1637-1648.
13.Ohno A, Jee JG, Fujiwara K, Tenno T, Goda N, Tochio H, Kobayashi H, Hiroaki H, Shirakawa M. Structure of the UBA domain of Dsk2p in complex with ubiquitin: molecular determinants for ubiquitin recognition. Structure 2005;13:521-532.
14.Varadan R, Assfalg M, Raasi S, Pickart C, Fushman D. Structural determinants for selective recognition of a Lys48-linked polyubiquitin chain by a UBA domain. Mol Cell 2005;18:687-698.
15.Moravcevic K, Mendrola JM, Schmitz KR, Wang YH, Slochower D, Janmey PA, Lemmon MA. Kinase associated-1 domains drive MARK/PAR1 kinases to membrane targets by binding acidic phospholipids. Cell 2010;143:966-977.
16.Jaleel M, Villa F, Deak M, Toth R, Prescott AR, Van Aalten DMF, Alessi DR. The ubiquitin-associated domain of AMPK-related kinases regulates conformation and LKB1-mediated phosphorylation and activation. Biochem J 2006;394:545-555.
17.Marx A, Nugoor C, Müller J, Panneerselvam S, Timm T, Bilang M, Mylonas E, Svergun DI, Mandelkow EM, Mandelkow E. Structural variations in the catalytic and ubiquitin-associated domains of microtubule-associated protein/microtubule affinity regulating kinase (MARK) 1 and MARK2. J Biol Chem 2006;281:27586-27599.
18.Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 1993;234(3):779-815.
19.Colovos C, Yeates TO. Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci 2008;2:1511-1519.
20.Vriend G, Sander C. Quality control of protein models: directional atomic contact analysis. J Appl Cryst 1993;26:47-60
21.Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC. GROMACS: fast, flexible, and free. J Comput Chem 2005;26:1701-1718.
22.Lindorff‐Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE. Improved side‐chain torsion potentials for the Amber ff99SB protein force field. Proteins 2010;78:1950-1958.
23.Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak J. Molecular dynamics with coupling to an external bath, J Chem Phys 1984;81: 3684-3690.
24.Parrinello M, Rahman A. Polymorphic transitions in single crystals: A new molecular dynamics method. J Appl Phys 1981;52:7182-7190.
25.Hess B, Bekker H, Berendsen HJC, Fraaije JGEM. LINCS: a linear constraint solver for molecular simulations. J Comp Chem 1997;18:1463-1472.
26.Darden T, York D, Pedersen L. Particle mesh Ewald: An N⋅ log (N) method for Ewald sums in large systems. J Chem Phys 1993;98: 10089-10092.
27.Spiliotopoulos D, Spitaleri A, Musco G. Exploring PHD fingers and H3K4me0 interactions with molecular dynamics simulations and binding free energy calculations: AIRE-PHD1, a comparative study. PloS One 2012;7:e46902.
28.Endicott JA, Noble ME, Johnson LN. The structural basis for control of eukaryotic protein kinases. Ann Rev Biochem 2012;81:587-613.
29.Johnson LN, Noble M, Owen DJ. Active and inactive protein kinases: structural basis for regulation. Cell 1996;85:149-158.
30.Nolen B, Taylor S, Ghosh G. Regulation of protein kinases: controlling activity through activation segment conformation. Mol Cell 2004;15:661-675.
31.Chen L, Jiao ZH, Zheng LS, Zhang YY, Xie ST, Wang ZX, Wu JW. Structural insight into the autoinhibition mechanism of AMP-activated protein kinase. Nature 2009;459:1146-1149.
32.Larkin M, Blackshields G, Brown N, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R. Clustal W and Clustal X version 2.0. Bioinformatics 2007;23:2947-2948.
33.Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605-1612.
34.Laskowski RA, Swindells MB. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 2011;51:2778-2786. | ||
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