The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
NEK2 phosphorylation site
Functional site description:
The NEK protein kinases are Never in mitosis A (NimA)-related kinases that belong to the NEK Serine/Threonine protein kinase family. NEKs have been identified in many Eukaryotes, where they play a critical role in cell cycle control. The closest mammalian NimA homologue NEK2 is a core component of the human centrosome and its activity and expression peak in S and G2 phase, during which it interacts with and phosphorylates several centrosomal proteins. NEK2 has many cell cycle-related functions, including cell cycle progression, spindle pole formation, microtubule anchoring, centriolar cohesion, cilia formation and chromatin condensation.
ELMs with same func. site: MOD_NEK2_1  MOD_NEK2_2 
ELM Description:
The optimal substrate motif of NEK2 was determined by positional scanning oriented peptide library screening (PS-OPLS) (Alexander,2011). The substrate motif targeted by NEK2 for phosphorylation shows the strongest amino acid selectivity in the -3 and +2 positions (relative to the Ser/Thr residue that is phosphorylated by NEK2). Having a preferred residue in the -3 position might compensate for the occurrence of less favorable residues in the +1 and +2 positions and vice versa. To encode this information, two variants of the motif have been defined, based on the selectivity for particular residues observed in the PS-OPLS experiment (Alexander,2011). The first variant of the NEK2 substrate phosphorylation motif contains Phe, Leu or Met in the -3 position. The occurrence of one of these residues, which are highly preferred to other hydrophobic residues, might compensate for less favored amino acids in the +1 and +2 positions. Hydrophilic amino acids as well as Ile and Val are strongly disfavored in the -3 position. In the -2 position, all amino acids except Pro are tolerated, although there is a slight preference for basic and hydrophobic residues. Similarly, in the -1 position there is no strong selectivity except for a strong discrimination against Pro. Also in the +1 position Pro is disfavored, together with the acidic Glu and Asp residues. The strong selection against Pro in this position allows discrimination against Cdk1 mitotic kinase phosphorylation sites. In the +2 position, the acidic residues Glu and Asp are not allowed, while a Pro residue is again accepted in this position. Although there seems to be a preference for particular hydrophobic residues in the +1 position and for specific amino acids in the +2 position, the occurrence of less favored residues in these two positions is allowed in this variant of the motif, as this might be compensated by the presence of the strongly selected Phe, Leu or Met in the -3 position.
Pattern: [FLM][^P][^P]([ST])[^DEP][^DE]
Pattern Probability: 0.0097983
Present in taxon: Eukaryota
Interaction Domain:
Pkinase (PF00069) Protein kinase domain (Stochiometry: 1 : 1)
o See 3 Instances for MOD_NEK2_1
o Abstract
NimA was initially identified in the filamentous fungus Aspergillus nidulans as a serine/threonine protein kinase vital for entry into mitosis (Oakley,1983). Kinases with structural and functional homology to NimA, known as NimA-related kinases (NEKs), have been identified throughout Eukaryotes, with higher Eukaryotes showing a significant expansion of the family. While a single NimA homologue exists in yeast, 2, 4 and 11 NimA-related kinases were identified in flies (D. melanogaster), worms (C. elegans) and Mammals, respectively (Moniz,2011). Of the human NEKs, NEK2 is most closely related to the fungal kinase. NEK2 is a cell cycle-regulated kinase with low activity in G1 phase, increased activity in S and G2 phase, and again diminished activity after mitotic onset. At the G1/S transition, the vertebrate NEK2 is expressed as two splice variants, NEK2A and NEK2B. Only the NEK2A variant contains the binding site necessary for substrate recognition, as well as a C-terminal destruction motif that mediates its APC/C dependent degradation.
During interphase and early mitosis, NEK2 is localised to the centrosome, where it phosphorylates many of it substrates at serine/threonine residues. Either inhibition of NEK2 catalytic activity or knock down of its substrates, including cNap1, rootletin or beta-catenin, inhibits centrosome separation, spindle assembly and formation of multinucleated cells. In kinetochores, knock down of NEK2 causes the displacement of the centromeric protein Mad2 from kinetochores and impairs chromosome segregation (Moniz,2011). NEK2-catalysed phosphorylation of the spindle assembly checkpoint component Hec1 regulates kinetochore-microtubule binding (Fry,2012). These studies indicate that NEK2 may coordinate cell division at multiple levels, and that deregulation of NEK2 causes centrosome abnormalities and aneuploidy. Other studies have shown that NEK2 is associated with disease progression in non-Hodgkin lymphomas.
o 12 selected references:

o 11 GO-Terms:

o 3 Instances for MOD_NEK2_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P51955 NEK2
NEK2_HUMAN
172 177 ILNHDTSFAKTFVGTPYYMS TP 2 Homo sapiens (Human)
1 
P40460 TID3
NDC80_YEAST
198 203 LKNLRYPFLESINKSQISAV TP 4 Saccharomyces cerevisiae S288c
1 
O14777 NDC80
NDC80_HUMAN
162 167 FKDLGYPFALSKSSMYTVGA TP 11 Homo sapiens (Human)
1 
Please cite: ELM 2016-data update and new functionality of the eukaryotic linear motif resource. (PMID:26615199)

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