AiPD: Autoinhibited Protein Database

Q9Z2B9

Gene name	Rps6ka4 (Msk2)
Protein name	Ribosomal protein S6 kinase alpha-4
Names	S6K-alpha-4 , EC 2.7.11.1 , 90 kDa ribosomal protein S6 kinase 4 , Nuclear mitogen- and stress-activated protein kinase 2 , RSK-like protein kinase , RLSK
Species	Mus musculus (Mouse)
KEGG Pathway	mmu:56613
EC number	2.7.11.1: Protein-serine/threonine kinases
Protein Class

Descriptions

The 90-kDa ribosomal S6 kinase 2 (RSK2) is broadly expressed in response to growth factors, peptide hormones, neurotransmitters, chemokines and other stimuli. RSK2 is a serine/threonine kinase containing two distinct catalytically functional kinase domains connected by a linker region. The C-terminal domain (CTD) phosphorylates the linker region and regulates the N-terminal domain, which phosphorylates various substrates. The scaffold of the RSK2 CTD is stabilized by the αL-helix, which is located underneath the catalytic cleft and embedded in the kinase scaffold. On the basis of this structure of the CTD of RSK2, ERKs are likely to be involved in abolishing the autoinhibitory function of the CTD. The ERKs binding site (residues 726-735) is located at the RSK2 C terminus close to the αL-helix (residues 697-712). Efficient activation of RSK2 requires interaction with extracellular signal-regulated protein kinases (ERKs) at a docking site in the RSK2 C terminus (residues 726-735) and subsequent phosphorylation of Thr-577 in the CTD T-activation loop.

Autoinhibitory domains (AIDs)

696-711 (Putative autoinhibitory alpha helix) SS

Target domain	396-674 (Protein kinase domain)
Relief mechanism	PTM, Partner binding
Assay

AID

696-711 (Putative autoinhibitory alpha helix)

Target domain

396-674 (Protein kinase domain)

Relief mechanism

PTM (Phosphorylation by ERK1/2), Partner binding (Binding of ERKs to C-terminal ERK-binding site (726-735))

Assay

Accessory elements

178-202 (Activation loop from InterPro)

Target domain	32-364 (Protein kinase domain)
Relief mechanism
Assay

550-574 (Activation loop from InterPro)

Target domain	410-674 (Protein kinase domain)
Relief mechanism
Assay

References

Li D et al. (2012) "Structural basis for the autoinhibition of the C-terminal kinase domain of human RSK1", Acta crystallographica. Section D, Biological crystallography, 68, 680-5

Li D et al. (2013) "The prometastatic ribosomal S6 kinase 2-cAMP response element-binding protein (RSK2-CREB) signaling pathway up-regulates the actin-binding protein fascin-1 to promote tumor metastasis", The Journal of biological chemistry, 288, 32528-32538

Malakhova M et al. (2008) "Structural basis for activation of the autoinhibitory C-terminal kinase domain of p90 RSK2", Nature structural & molecular biology, 15, 112-3

Poteet-Smith CE et al. (1999) "Generation of constitutively active p90 ribosomal S6 kinase in vivo. Implications for the mitogen-activated protein kinase-activated protein kinase family", The Journal of biological chemistry, 274, 22135-8

Autoinhibited structure

Activated structure

1 structures for Q9Z2B9

Entry ID	Method	Resolution	Chain	Position	Source
AF-Q9Z2B9-F1	Predicted				AlphaFoldDB

38 variants for Q9Z2B9

Variant ID(s)	Position	Change	Diseaes Association	Provenance
rs262972806	7	D>E	No	EVA
rs3389515742	41	T>A	No	EVA
rs3389514924	41	T>M	No	EVA
rs3389479357	86	R>S	No	EVA
rs3389533513	184	K>M	No	EVA
rs3409104722	229	F>L	No	EVA
rs3408825708	229	F>V	No	EVA
rs3408833499	229	F>Y	No	EVA
rs3406981088	231	L>Q	No	EVA
rs3389526732	233	T>I	No	EVA
rs3389501184	239	T>I	No	EVA
rs3389469311	244	R>G	No	EVA
rs3389538039	264	R>L	No	EVA
rs3389532796	270	Q>*	No	EVA
rs3389526777	278	C>Y	No	EVA
rs3389521919	289	P>S	No	EVA
rs3407911566	321	Q>H	No	EVA
rs3408825712	323	R>H	No	EVA
rs243226128	390	R>K	No	EVA
rs3389515793	438	A>V	No	EVA
rs228428009	455	A>T	No	EVA
rs3389533516	463	H>Y	No	EVA
rs3408825684	483	L>Q	No	EVA
rs3389526722	489	G>E	No	EVA
rs3389469268	505	E>K	No	EVA
rs3389501264	512	S>G	No	EVA
rs3389526760	535	N>K	No	EVA
rs3389501265	541	D>Y	No	EVA
rs3389532782	545	A>V	No	EVA
rs3389514940	547	V>L	No	EVA
rs3389514253	554	F>L	No	EVA
rs3389501238	594	S>R	No	EVA
rs3412670694	602	M>I	No	EVA
rs3409302977	667	G>E	No	EVA
rs3389514329	681	S>F	No	EVA
rs3389526744	686	R>L	No	EVA
rs3389469300	704	A>V	No	EVA
rs212273698	738	A>V	No	EVA

No associated diseases with Q9Z2B9

9 regional properties for Q9Z2B9

Type	Name	Position	InterPro Accession
domain	Protein kinase domain	33 - 301	IPR000719-1
domain	Protein kinase domain	411 - 674	IPR000719-2
domain	AGC-kinase, C-terminal	302 - 371	IPR000961
active_site	Serine/threonine-protein kinase, active site	157 - 169	IPR008271-1
active_site	Serine/threonine-protein kinase, active site	526 - 538	IPR008271-2
binding_site	Protein kinase, ATP binding site	39 - 65	IPR017441-1
binding_site	Protein kinase, ATP binding site	417 - 440	IPR017441-2
domain	Protein kinase, C-terminal	322 - 361	IPR017892
domain	MSK2, N-terminal catalytic domain	32 - 364	IPR037714

Functions

		Description
EC Number	2.7.11.1	Protein-serine/threonine kinases
Subcellular Localization	Nucleus
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

5 GO annotations of cellular component

Name	Definition
cytoplasm	The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.
cytosol	The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
nucleoplasm	That part of the nuclear content other than the chromosomes or the nucleolus.
nucleus	A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated. In most cells, the nucleus contains all of the cell's chromosomes except the organellar chromosomes, and is the site of RNA synthesis and processing. In some species, or in specialized cell types, RNA metabolism or DNA replication may be absent.
synapse	The junction between an axon of one neuron and a dendrite of another neuron, a muscle fiber or a glial cell. As the axon approaches the synapse it enlarges into a specialized structure, the presynaptic terminal bouton, which contains mitochondria and synaptic vesicles. At the tip of the terminal bouton is the presynaptic membrane; facing it, and separated from it by a minute cleft (the synaptic cleft) is a specialized area of membrane on the receiving cell, known as the postsynaptic membrane. In response to the arrival of nerve impulses, the presynaptic terminal bouton secretes molecules of neurotransmitters into the synaptic cleft. These diffuse across the cleft and transmit the signal to the postsynaptic membrane.

6 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
histone H3S10 kinase activity	Catalysis of the reaction
histone H3S28 kinase activity	Catalysis of the reaction
magnesium ion binding	Binding to a magnesium (Mg) ion.
protein serine kinase activity	Catalysis of the reactions
protein serine/threonine kinase activity	Catalysis of the reactions

7 GO annotations of biological process

Name	Definition
inflammatory response	The immediate defensive reaction (by vertebrate tissue) to infection or injury caused by chemical or physical agents. The process is characterized by local vasodilation, extravasation of plasma into intercellular spaces and accumulation of white blood cells and macrophages.
interleukin-1-mediated signaling pathway	The series of molecular signals initiated by interleukin-1 binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription.
intracellular signal transduction	The process in which a signal is passed on to downstream components within the cell, which become activated themselves to further propagate the signal and finally trigger a change in the function or state of the cell.
positive regulation of transcription by RNA polymerase II	Any process that activates or increases the frequency, rate or extent of transcription from an RNA polymerase II promoter.
post-translational protein modification	The process of covalently altering one or more amino acids in a protein after the protein has been completely translated and released from the ribosome.
protein phosphorylation	The process of introducing a phosphate group on to a protein.
regulation of DNA-templated transcription	Any process that modulates the frequency, rate or extent of cellular DNA-templated transcription.

19 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
P18652	RPS6KA	Ribosomal protein S6 kinase 2 alpha	Gallus gallus (Chicken)	SS
Q5F3L1	RPS6KA5	Ribosomal protein S6 kinase alpha-5	Gallus gallus (Chicken)	SS
Q9UK32	RPS6KA6	Ribosomal protein S6 kinase alpha-6	Homo sapiens (Human)	SS
Q96S38	RPS6KC1	Ribosomal protein S6 kinase delta-1	Homo sapiens (Human)	PR
P51812	RPS6KA3	Ribosomal protein S6 kinase alpha-3	Homo sapiens (Human)	EV
Q15349	RPS6KA2	Ribosomal protein S6 kinase alpha-2	Homo sapiens (Human)	SS
Q15418	RPS6KA1	Ribosomal protein S6 kinase alpha-1	Homo sapiens (Human)	EV
O75582	RPS6KA5	Ribosomal protein S6 kinase alpha-5	Homo sapiens (Human)	SS
O75676	RPS6KA4	Ribosomal protein S6 kinase alpha-4	Homo sapiens (Human)	SS
Q8BLK9	Rps6kc1	Ribosomal protein S6 kinase delta-1	Mus musculus (Mouse)	PR
P18653	Rps6ka1	Ribosomal protein S6 kinase alpha-1	Mus musculus (Mouse)	SS
P18654	Rps6ka3	Ribosomal protein S6 kinase alpha-3	Mus musculus (Mouse)	SS
Q9WUT3	Rps6ka2	Ribosomal protein S6 kinase alpha-2	Mus musculus (Mouse)	SS
Q8C050	Rps6ka5	Ribosomal protein S6 kinase alpha-5	Mus musculus (Mouse)	PR
Q9Z1M4	Rps6kb2	Ribosomal protein S6 kinase beta-2	Mus musculus (Mouse)	SS
Q8BSK8	Rps6kb1	Ribosomal protein S6 kinase beta-1	Mus musculus (Mouse)	SS
Q63531	Rps6ka1	Ribosomal protein S6 kinase alpha-1	Rattus norvegicus (Rat)	SS
Q21734	rskn-1	Putative ribosomal protein S6 kinase alpha-1	Caenorhabditis elegans	SS
Q18846	rskn-2	Putative ribosomal protein S6 kinase alpha-2	Caenorhabditis elegans	PR

10	20	30	40	50	60
MGDEDEDEGC	AVELQITEAN	LTGHEEKVSV	ENFALLKVLG	TGAYGKVFLV	RKTGGHDAGK
70	80	90	100	110	120
LYAMKVLRKA	ALVQRAKTQE	HTRTERSVLE	LVRQAPFLVT	LHYAFQTDAK	LHLILDYVSG
130	140	150	160	170	180
GEMFTHLYQR	QYFKEAEVRV	YGGEIVLALE	HLHKLGIIYR	DLKLENVLLD	SEGHIVLTDF
190	200	210	220	230	240
GLSKEFLTEE	KERTFSFCGT	IEYMAPEIIR	SKAGHGKAVD	WWSLGILLFE	LLTGASPFTL
250	260	270	280	290	300
EGERNTQAEV	SRRILKCSPP	FPLRIGPVAQ	DLLQRLLCKD	PKKRLGAGPQ	GAQEVKSHPF
310	320	330	340	350	360
FQGLDWVALA	ARKIPAPFRP	QIRSELDVGN	FAEEFTRLEP	VYSPAGSPPP	GDPRIFQGYS
370	380	390	400	410	420
FVAPSILFDH	NNAVMADVLQ	APGAGYRPGR	AAVARSAMMQ	DSPFFQQYEL	DLREPALGQG
430	440	450	460	470	480
SFSVCRRCRQ	RQSGQEFAVK	ILSRRLEENT	QREVAALRLC	QSHPNVVNLH	EVLHDQLHTY
490	500	510	520	530	540
LVLELLRGGE	LLEHIRKKRL	FSESEASQIL	RSLVSAVSFM	HEEAGVVHRD	LKPENILYAD
550	560	570	580	590	600
DTPGAPVKII	DFGFARLRPQ	SPAEPMQTPC	FTLQYAAPEL	LAQQGYDESC	DLWSLGVILY
610	620	630	640	650	660
MMLSGQVPFQ	GASGQGGQSQ	AAEIMCKIRE	GRFSLDGEAW	QGVSEEAKEL	VRGLLTVDPA
670	680	690	700	710	720
KRLKLEGLRS	SSWLQDGSAR	SSPPLRTPDV	LESSGPAVRS	GLNATFMAFN	RGKREGFFLK
730	740	750	760	770
SVENAPLAKR	RKQKLRSAAA	SRRGSPVPAS	SGRLPASAAK	GTTRRANGPL	SPS