Microtubule Affinity-Regulating Kinase 4: Structure, Function, and Regulation
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REVIEW PAPER
Microtubule Affinity-Regulating Kinase 4: Structure, Function, and Regulation Farha Naz • Farah Anjum • Asimul Islam Faizan Ahmad • Md. Imtaiyaz Hassan
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Ó Springer Science+Business Media New York 2013
Abstract MAP/Microtubule affinity-regulating kinase 4 (MARK4) belongs to the family of serine/threonine kinases that phosphorylate the microtubule-associated proteins (MAP) causing their detachment from the microtubules thereby increasing microtubule dynamics and facilitating cell division, cell cycle control, cell polarity determination, cell shape alterations, etc. The MARK4 gene encodes two alternatively spliced isoforms, L and S that differ in their C-terminal region. These isoforms are differentially regulated in human tissues including central nervous system. MARK4L is a 752-residue-long polypeptide that is divided into three distinct domains: (1) protein kinase domain (59–314), (2) ubiquitin-associated domain (322–369), and (3) kinase-associated domain (703–752) plus 54 residues (649–703) involved in the proper folding and function of the enzyme. In addition, residues 65–73 are considered to be the ATP-binding domain and Lys88 is considered as ATP-binding site. Asp181 has been proposed to be the active site of MARK4 that is activated by phosphorylation of Thr214 side chain. The isoform MARK4S is highly expressed in the normal brain and is presumably involved in neuronal differentiation. On the other hand, the isoform MARK4L is upregulated in hepatocarcinoma cells and gliomas suggesting its involvement in cell cycle. Several biological functions are also associated with MARK4 including microtubule bundle formation, nervous system development, and positive regulation of programmed cell F. Naz A. Islam F. Ahmad Md. I. Hassan (&) Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India e-mail: [email protected] F. Anjum Female College of Applied Medical Science, Taif University, Al-Taif, Kingdom of Saudi Arabia
death. Therefore, MARK4 is considered as the most suitable target for structure-based rational drug design. Our sequence, structure- and function-based analysis should be helpful for better understanding of mechanisms of regulation of microtubule dynamics and MARK4 associated diseases. Keywords Microtubule affinity-regulating kinase Microtubule dynamics Tumor proliferation Microtubule-associated protein Cell differentiation Cell polarity Alzheimer’s disease
Introduction The protein homologs PAR-1 (partition-defective), KIN1, and MARK (MAP/Microtubule affinity-regulating kinase) belonging to the Ser/Thr protein kinase family are basically involved in cell polarity, microtubules stability, protein stability, intracellular signaling, cell cycle control, cell division, and Alzheimer disease (AD), etc. [1]. These proteins share conserved primary structural organization consisting of four distinct structural domains, namely catalytic kinase domain, ubiquitin-associated domain, kinaseassociated domain, and ATP-binding
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