Phosphatase Subfamily PTPN5 RR

Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPN5_RR

PTPN5_RR is a tyrosine-specific phosphatase subfamily that regulates ERK signaling. Uniquely, some members are non-receptors, while others have receptor and non-receptor isoforms. It is characterized by a kinase interaction motif (KIM), which is regulated by the phosphorylation state of a serine within the motif. Human members are particularly abundant in spleen, thymus, and different parts of the brain.

Evolution

The PTPN5_RR subfamily emerged in eumetazoa and duplicated in vertebrates but is lost in nematodes. Human has three members: PTPN5 (STEP), PTPN7 (HePTP), and PTPRR (PTP-SL).

Domains

PTPN5_RR members have an N-terminal kinase interaction motif (KIM) (~16 aa) [1] and a C-terminal phosphatase domain. Vertebrate PTP5RR has a signal peptide and TM region upstream from these domains, while PTPN7 has a TM but no signal peptide. Some but not all invertebrate homologs contain a SigP.

KIM mediates an interaction with ERK MAP kinases and with p53. The KIM contains a serine that can be phosphorylated by PKA. The phosphorylation state of this serine affects the binding between phosphatases to ERK MAP kinases ERK and to p53.

Several PTPN5 crystal structures have been solved [2, 3, 4, 5]. An additional helix H0 was found in mouse PTPRR and human PTPN7. The H0 of mouse PTPRR supports the site of phosphorylation at Thr253 when PTPRR interacts with ERK2 or p38. The H0 of PTPRR and PTPN7 do not align with each other in structure, and PTPN5 does not have H0.

The longest isoform of human PTPN5 has two proline-rich regions [6].

Functions

Human has three members: PTPN5, PTPN7 and PTPRR. Though PTPN5 and PTPN7 are named as non-receptor PTPs, at least some of their isoforms contain predicted transmembrane region or have been show to associate with membranes. All the three are abundantly expressed in brain: PTPN5 is mainly expressed in striatum and nucleus accumbens, which are part of the basal ganglia; in contrast, PTPRR is mainly expressed in cerebellum; PTPN7 is most abundantly expressed in thyroid, spleen, a nd whole blood, and it is also expressed at a lower level in the striatum and nucleus accumbens .

All three human proteins act as physiological regulators of the ERK1/2 signaling pathway. For PTPN7 and PTPRR, upon their binding to ERK1/2, their N-terminal domains were phosphorylated by ERK1/2 at the same positions (which are occupied by different amino acid in PTPN5), whereas they dephosphorylated the regulatory phosphotyrosine residues of ERK1/2 and inactivated ERK1/2 [3, 5, 7]. The interactions between PTPN7 and ERK, and PTPRR and ERK are mediated by kinase interaction motif (KIM). A serine residue in the KIM is phosphorylated by PKA (cAMP-dependent protein kinase) and dephosphorylated by some serine phosphatase, which rapidly affect the ability of PTPN7 and PTPRR binding to ERK and p38, and change in response to external stimuli. Although PTPN5/STEP does not have the residues phoshorylated by ERK, it has the KIM domain and the serine phosphorylated by PKA in PTPN7 and PTPRR.

Drosophila PTP-ER also acts as a MAPK phosphatase downstream of ras.

PTPN5 (STEP)

PTPN5 is also termed as "striatum enriched phosphatase" (STEP), since it is highly enriched within the striatum relative to other brain areas [8]. This expression pattern is consistent with GTEx. PTPN5 is most abundantly expressed in striatum (including caudate and putamen) and nucleus accumbens, which are part though not all of basal ganglia. It is not surprised that PTPN5 is related to long-term memories, neuroplasticity [9] and development of stress-related cognitive and morphological changes [10], and its abnormality is related to Alzheimer's dieases [11, 12] and schizophrenia [13] (controversial, though, e.g. see [14]). PTPN5 has 6 isoforms in Entrez database, which may have different functions. In particular, it is named as non-receptor PTP, but some of its isoforms have predicted transmembrane region. PTPN5 have various substrates, including:

• ERK1/2 as shown above [7].

• Fyn, a kinase of Src family. PTPN5 also regulates the activity of Fyn kinase by specifically dephosphorylating the regulatory Tyr420 but not at Tyr531. A membrane-associated isoform of PTPN5, STEP(61), located in the postsynaptic densities (PSDs) of striatal neurons. STEP(61) associates with Fyn which is also enriched in PSDs. A substrate-trapping variant (STEP(61) CS) binds to Fyn but not to other members of the Src family present in PSDs. STEP(61) binds to Fyn through one of its proline-rich domains and the kinase-interacting motif domain, whereas Fyn binds to STEP(61) through its Src homology 2 domain and the unique N-terminal domain [6].

• NR2B, NMDA receptor subunit. PTPN5 dephoshorylates NMDA receptor subunits and increases NMDA receptor endocytosis, which may contribute to the cognitive deficits in Alzheimer's disease. Amyloid beta mediate the accumulation of STEP(61), dephosphorylation of Tyr1472 of the NR2B subunit, and decreased NR1 and NR2B subunits on neuronal membranes. The underlying mechanism is unclear, but perhaps related to the ubiquitin proteasome system [11, 12].

• PTPRA at its regulatory Tyr-789 [15].

PTPN7 (HePTP/LC-PTP)

PTPN7 is a cytoplasmic protein tyrosine phosphatase whose expression is induced by mitogenic stimuli. It is also called hematopoietic tyrosine phosphatase (HePTP) or leukocyte PTP (LC-PTP), because it is most abundantly expressed in spleen, thyroid, and whole blood cells (including T cells, B cells, mast cells and etc) [16, 17, 18]. It is also expressed in striatum and nucleus accumbens, ardrenal gland, small intestine but at the same level as spleen, thyroid and whole blood (GTEX).

PTPN7 regulates the activity and translocation [19] of the MAP kinases Erk and p38, but not JNK [20, 21, 22, 23], particularly in T cell antigen receptor (TCR) signaling [20, 24]. It binds Erk and p38 via a short, highly conserved motif in its N-terminal kinase interaction motfi (KIM) from 142 to 157. Association via the KIM results in an unusual, reciprocal interaction between the two proteins. First, Erk phosphorylates PTPN7 at residues Thr171 and Ser198 (Thr45 and Ser72 in the paper [3] Figure 3a). Second, HePTP dephosphorylates Erk at pTyr185. According to crystal structure, both reactions require significant conformational changes in both proteins [3, 4]. The mechanism is similar to that of PTPRR as well as ERK-specific MKPs [5]. (Note: The two phosphorylated site Thr171 and Ser198 are observed in PTPN7 and PTPRR but not PTPN5.)

PTPN7 is under continuous control by PKA (cAMP-dependent protein kinase) and a serine-specific phosphatase, probably PP1, in T-cells, through phosphorylation at Ser-149, which locates in KIM (142-157) mediates the binding between PTPN7 and ERK and p39. This phosphorylation can there rapidly affect the ability of PTPN7 to inhibit the ERK and p38 MAP kinases, and change in response to external stimuli [25].

PTPN7 is amplified and overexpressed in myeloid malignancies, which implies it may promote abnormal myeloid cell growth [26].

It is worthy pointing out that PTPN7 has PTP activity, although it has substitution at N replaced by D at KNRY motif.

PTPRR (EC-PTP/PTP-SL/PTPBR7)

PTPRR is mainly expressed in brain [27, 28, 29]. In particular, according to GTEx, it is most abundantly expressed in cerebellum (cerebellum and cerebellar hemisphere in GTEx); it is also expressed in other parts of brain but at lower level. Besides brain, PTPRR is also expressed in uterus, bladder, and traverse colon (interestingly not sigmoid colon). Like PTPN5, PTPRR has multiple isoforms, each of which has a unique expression pattern in specific cell populations as well as in tissue regions as shown in mouse [30]. PTPRR dephosphorylates ERKs:

• ERK1/2. A sequence of 16 amino acids in PTPRR/PTP-SL was identified as being critical for ERK1/2 binding and termed kinase interaction motif (KIM) at 331-346 (224-239 in [7]). The KIM is conserved Figure 13B in [7]. Ser338 (Ser231 in paper [31]) within KIM is phosphorylated by cAMP-dependent protein kinase A (PKA) is critical for binding to ERK1/2 [31]. The binding is required for phosphorylation of PTPRR (PTP-SL) by ERK1/2 at Thr361 (Thr253 in paper) [5, 7, 32, 33]. Based upon crystal structure of PTPRR-ERK2 complex, the subsequent dephosphorylation of ERK2 seems to be possible only if a conformational rearrangement of the two interacting partners takes place [5] (Note 1:. this is similar to MKP of DSP family). (Note 2: The KIM locates at PTPN5:238-253, PTPN7:142-157, PTPRR:331-346, according to the sequences in phosphatome.net database. The phosphorylated Thr361 is not conserved, which aligned to Thr171 in PTPN7 but Ser268 in PTPN5.)

• ERK5 (?) PTPRR can bind to ERK5, down-regulate endogenous ERK5 activity, and impede the translocation of ERK5 to the nucleus. On the other hand, PTPRR is a substrate of ERK5 and independent of phosphorylation binding to the kinase enhances its catalytic phosphatase activity [34]. But, there is no direct evidence that PTPRR dephosphorylates ERK5 on specific residues.

PTPRR also functions in cancer. Methylation of the PTPRR promoter has a role in metastasis and may be a biomarker of invasive cervical cancer [35]. It is also an early and frequent target of silencing in human colorectal tumorigenesis [36].

References

1. Francis DM, Koveal D, Tortajada A, Page R, and Peti W. Interaction of kinase-interaction-motif protein tyrosine phosphatases with the mitogen-activated protein kinase ERK2. PLoS One. 2014;9(3):e91934. DOI:10.1371/journal.pone.0091934 |
2. Eswaran J, von Kries JP, Marsden B, Longman E, Debreczeni JE, Ugochukwu E, Turnbull A, Lee WH, Knapp S, and Barr AJ. Crystal structures and inhibitor identification for PTPN5, PTPRR and PTPN7: a family of human MAPK-specific protein tyrosine phosphatases. Biochem J. 2006 May 1;395(3):483-91. DOI:10.1042/BJ20051931 |
3. Mustelin T, Tautz L, and Page R. Structure of the hematopoietic tyrosine phosphatase (HePTP) catalytic domain: structure of a KIM phosphatase with phosphate bound at the active site. J Mol Biol. 2005 Nov 18;354(1):150-63. DOI:10.1016/j.jmb.2005.09.049 |
4. Critton DA, Tortajada A, Stetson G, Peti W, and Page R. Structural basis of substrate recognition by hematopoietic tyrosine phosphatase. Biochemistry. 2008 Dec 16;47(50):13336-45. DOI:10.1021/bi801724n |
5. Szedlacsek SE, Aricescu AR, Fulga TA, Renault L, and Scheidig AJ. Crystal structure of PTP-SL/PTPBR7 catalytic domain: implications for MAP kinase regulation. J Mol Biol. 2001 Aug 17;311(3):557-68. DOI:10.1006/jmbi.2001.4890 |
6. Nguyen TH, Liu J, and Lombroso PJ. Striatal enriched phosphatase 61 dephosphorylates Fyn at phosphotyrosine 420. J Biol Chem. 2002 Jul 5;277(27):24274-9. DOI:10.1074/jbc.M111683200 |
7. Pulido R, Zúñiga A, and Ullrich A. PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J. 1998 Dec 15;17(24):7337-50. DOI:10.1093/emboj/17.24.7337 |
8. Lombroso PJ, Murdoch G, and Lerner M. Molecular characterization of a protein-tyrosine-phosphatase enriched in striatum. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7242-6. DOI:10.1073/pnas.88.16.7242 |
9. Olausson P, Venkitaramani DV, Moran TD, Salter MW, Taylor JR, and Lombroso PJ. The tyrosine phosphatase STEP constrains amygdala-dependent memory formation and neuroplasticity. Neuroscience. 2012 Dec 6;225:1-8. DOI:10.1016/j.neuroscience.2012.07.069 |
10. Yang CH, Huang CC, and Hsu KS. A critical role for protein tyrosine phosphatase nonreceptor type 5 in determining individual susceptibility to develop stress-related cognitive and morphological changes. J Neurosci. 2012 May 30;32(22):7550-62. DOI:10.1523/JNEUROSCI.5902-11.2012 |
11. Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, and Lombroso PJ. Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neurosci. 2010 Apr 28;30(17):5948-57. DOI:10.1523/JNEUROSCI.0157-10.2010 |
12. Zhang Y, Kurup P, Xu J, Anderson GM, Greengard P, Nairn AC, and Lombroso PJ. Reduced levels of the tyrosine phosphatase STEP block β amyloid-mediated GluA1/GluA2 receptor internalization. J Neurochem. 2011 Nov;119(3):664-72. DOI:10.1111/j.1471-4159.2011.07450.x |
13. Pelov I, Teltsh O, Greenbaum L, Rigbi A, Kanyas-Sarner K, Lerer B, Lombroso P, and Kohn Y. Involvement of PTPN5, the gene encoding the striatal-enriched protein tyrosine phosphatase, in schizophrenia and cognition. Psychiatr Genet. 2012 Aug;22(4):168-76. DOI:10.1097/YPG.0b013e3283518586 |
14. Lanz TA, Joshi JJ, Reinhart V, Johnson K, Grantham LE 2nd, and Volfson D. STEP levels are unchanged in pre-frontal cortex and associative striatum in post-mortem human brain samples from subjects with schizophrenia, bipolar disorder and major depressive disorder. PLoS One. 2015;10(3):e0121744. DOI:10.1371/journal.pone.0121744 |
15. Xu J, Kurup P, Foscue E, and Lombroso PJ. Striatal-enriched protein tyrosine phosphatase regulates the PTPα/Fyn signaling pathway. J Neurochem. 2015 Aug;134(4):629-41. DOI:10.1111/jnc.13160 |
16. Adachi M, Sekiya M, Isobe M, Kumura Y, Ogita Z, Hinoda Y, Imai K, and Yachi A. Molecular cloning and chromosomal mapping of a human protein-tyrosine phosphatase LC-PTP. Biochem Biophys Res Commun. 1992 Aug 14;186(3):1607-15. DOI:10.1016/s0006-291x(05)81592-x |
17. Zanke B, Suzuki H, Kishihara K, Mizzen L, Minden M, Pawson A, and Mak TW. Cloning and expression of an inducible lymphoid-specific, protein tyrosine phosphatase (HePTPase). Eur J Immunol. 1992 Jan;22(1):235-9. DOI:10.1002/eji.1830220134 |
18. Swieter M, Berenstein EH, Swaim WD, and Siraganian RP. Aggregation of IgE receptors in rat basophilic leukemia 2H3 cells induces tyrosine phosphorylation of the cytosolic protein-tyrosine phosphatase HePTP. J Biol Chem. 1995 Sep 15;270(37):21902-6. DOI:10.1074/jbc.270.37.21902 |
19. Pettiford SM and Herbst R. The protein tyrosine phosphatase HePTP regulates nuclear translocation of ERK2 and can modulate megakaryocytic differentiation of K562 cells. Leukemia. 2003 Feb;17(2):366-78. DOI:10.1038/sj.leu.2402767 |
20. Saxena M, Williams S, Gilman J, and Mustelin T. Negative regulation of T cell antigen receptor signal transduction by hematopoietic tyrosine phosphatase (HePTP). J Biol Chem. 1998 Jun 19;273(25):15340-4. DOI:10.1074/jbc.273.25.15340 |
21. Oh-hora M, Ogata M, Mori Y, Adachi M, Imai K, Kosugi A, and Hamaoka T. Direct suppression of TCR-mediated activation of extracellular signal-regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific phosphatase. J Immunol. 1999 Aug 1;163(3):1282-8.
22. Gronda M, Arab S, Iafrate B, Suzuki H, and Zanke BW. Hematopoietic protein tyrosine phosphatase suppresses extracellular stimulus-regulated kinase activation. Mol Cell Biol. 2001 Oct;21(20):6851-8. DOI:10.1128/MCB.21.20.6851-6858.2001 |
23. Muñoz JJ, Tárrega C, Blanco-Aparicio C, and Pulido R. Differential interaction of the tyrosine phosphatases PTP-SL, STEP and HePTP with the mitogen-activated protein kinases ERK1/2 and p38alpha is determined by a kinase specificity sequence and influenced by reducing agents. Biochem J. 2003 May 15;372(Pt 1):193-201. DOI:10.1042/BJ20021941 |
24. Saxena M, Williams S, Brockdorff J, Gilman J, and Mustelin T. Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J Biol Chem. 1999 Apr 23;274(17):11693-700. DOI:10.1074/jbc.274.17.11693 |
25. Nika K, Hyunh H, Williams S, Paul S, Bottini N, Taskén K, Lombroso PJ, and Mustelin T. Haematopoietic protein tyrosine phosphatase (HePTP) phosphorylation by cAMP-dependent protein kinase in T-cells: dynamics and subcellular location. Biochem J. 2004 Mar 1;378(Pt 2):335-42. DOI:10.1042/BJ20031244 |
26. Zanke B, Squire J, Griesser H, Henry M, Suzuki H, Patterson B, Minden M, and Mak TW. A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1. Leukemia. 1994 Feb;8(2):236-44.
27. Sharma E and Lombroso PJ. A neuronal protein tyrosine phosphatase induced by nerve growth factor. J Biol Chem. 1995 Jan 6;270(1):49-53. DOI:10.1074/jbc.270.1.49 |
28. Sharma E and Lombroso PJ. A neuronal protein tyrosine phosphatase induced by nerve growth factor. J Biol Chem. 1995 Jan 6;270(1):49-53. DOI:10.1074/jbc.270.1.49 |
29. Shiozuka K, Watanabe Y, Ikeda T, Hashimoto S, and Kawashima H. Cloning and expression of PCPTP1 encoding protein tyrosine phosphatase. Gene. 1995 Sep 11;162(2):279-84. DOI:10.1016/0378-1119(95)00306-q |
30. Augustine KA, Silbiger SM, Bucay N, Ulias L, Boynton A, Trebasky LD, and Medlock ES. Protein tyrosine phosphatase (PC12, Br7,S1) family: expression characterization in the adult human and mouse. Anat Rec. 2000 Mar 1;258(3):221-34. DOI:10.1002/(SICI)1097-0185(20000301)258:3<221::AID-AR1>3.0.CO;2-W |
31. Blanco-Aparicio C, Torres J, and Pulido R. A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase. J Cell Biol. 1999 Dec 13;147(6):1129-36. DOI:10.1083/jcb.147.6.1129 |
32. Ogata M, Oh-hora M, Kosugi A, and Hamaoka T. Inactivation of mitogen-activated protein kinases by a mammalian tyrosine-specific phosphatase, PTPBR7. Biochem Biophys Res Commun. 1999 Mar 5;256(1):52-6. DOI:10.1006/bbrc.1999.0278 |
33. Zúñiga A, Torres J, Ubeda J, and Pulido R. Interaction of mitogen-activated protein kinases with the kinase interaction motif of the tyrosine phosphatase PTP-SL provides substrate specificity and retains ERK2 in the cytoplasm. J Biol Chem. 1999 Jul 30;274(31):21900-7. DOI:10.1074/jbc.274.31.21900 |
34. Buschbeck M, Eickhoff J, Sommer MN, and Ullrich A. Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway. J Biol Chem. 2002 Aug 16;277(33):29503-9. DOI:10.1074/jbc.M202149200 |
35. Su PH, Lin YW, Huang RL, Liao YP, Lee HY, Wang HC, Chao TK, Chen CK, Chan MW, Chu TY, Yu MH, and Lai HC. Epigenetic silencing of PTPRR activates MAPK signaling, promotes metastasis and serves as a biomarker of invasive cervical cancer. Oncogene. 2013 Jan 3;32(1):15-26. DOI:10.1038/onc.2012.29 |
36. Menigatti M, Cattaneo E, Sabates-Bellver J, Ilinsky VV, Went P, Buffoli F, Marquez VE, Jiricny J, and Marra G. The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis. Mol Cancer. 2009 Dec 16;8:124. DOI:10.1186/1476-4598-8-124 |

Supplementary information

The position in this page is numbered by the sequences below:

>PTPN5 CC1:CC1:PTP:PTPN5_RR [Homo sapiens] MNYEGARSERENHAADDSEGGALDMCCSERLPGLPQPIVMEALDEAEGLQDSQREMPPPPPPSPPSDPAQKPPPRGAGSHSLTVRSSLCLFAASQFLLACGVLWFSGYGHIWSQNATNLVSSLLTLLKQLEPTAWLDSGTWGVPSLLLVFLSVGLVLVTTLVWHLLRTPPEPPTPLPPEDRRQSVSRQPSFTYSEWMEEKIEDDFLDLDPVPETPVFDCVMDIKPEADPTSLTVKSMGLQERRGSNVSLTLDMCTPGCNEEGFGYLMSPREESAREYLLSASRVLQAEELHEKALDPFLLQAEFFEIPMNFVDPKEYDIPGLVRKNRYKTILPNPHSRVCLTSPDPDDPLSSYINANYIRGYGGEEKVYIATQGPIVSTVADFWRMVWQEHTPIIVMITNIEEMNEKCTEYWPEEQVAYDGVEITVQKVIHTEDYRLRLISLKSGTEERGLKHYWFTSWPDQKTPDRAPPLLHLVREVEEAAQQEGPHCAPIIVHCSAGIGRTGCFIATSICCQQLRQEGVVDILKTTCQLRQDRGGMIQTCEQYQFVHHVMSLYEKQLSHQSPE

>PTPN7 CC1:CC1:PTP:PTPN5_RR [Homo sapiens] MVGKAWPLTHSQGTGPWAPEGHRREAADPWWQRQQAQEGRMQLGCAWVAARRGGGRKLASWSLLSPQRQTDRQTDSWQEAAWGPQLLQQTSWLSEPPLGPAPHLSMVQAHGGRSRAQPLTLSLGAAMTQPPPEKTPAKKHVRLQERRGSNVALMLDVRSLGAVEPICSVNTPREVTLHFLRTAGHPLTRWALQRQPPSPKQLEEEFLKIPSNFVSPEDLDIPGHASKDRYKTILPNPQSRVCLGRAQSQEDGDYINANYIRGYDGKEKVYIATQGPMPNTVSDFWEMVWQEEVSLIVMLTQLREGKEKCVHYWPTEEETYGPFQIRIQDMKECPEYTVRQLTIQYQEERRSVKHILFSAWPDHQTPESAGPLLRLVAEVEESPETAAHPGPIVVHCSAGIGRTGCFIATRIGCQQLKARGEVDILGIVCQLRLDRGGMIQTAEQYQFLHHTLALYAGQLPEEPSP

>PTPRR CC1:CC1:PTP:PTPN5_RR [Homo sapiens] MRRAVCFPALCLLLNLHAAGCFSGNNDHFLAINQKKSGKPVFIYKHSQDIEKSLDIAPQKIYRHSYHSSSEAQVSKRHQIVNSAFPRPAYDPSLNLLAMDGQDLEVENLPIPAANVIVVTLQMDVNKLNITLLRIFRQGVAAALGLLPQQVHINRLIGKKNSIELFVSPINRKTGISDALPSEEVLRSLNINVLHQSLSQFGITEVSPEKNVLQGQHEADKIWSKEGFYAVVIFLSIFVIIVTCLMILYRLKERFQLSLRQDKEKNQEIHLSPITLQPALSEAKTVHSMVQPEQAPKVLNVVVDPQGRGAPEIKATTATSVCPSPFKMKPIGLQERRGSNVSLTLDMSSLGNIEPFVSIPTPREKVAMEYLQSASRILTRSQLRDVVASSHLLQSEFMEIPMNFVDPKEIDIPRHGTKNRYKTILPNPLSRVCLRPKNVTDSLSTYINANYIRGYSGKEKAFIATQGPMINTVDDFWQMVWQEDSPVIVMITKLKEKNEKCVLYWPEKRGIYGKVEVLVISVNECDNYTIRNLVLKQGSHTQHVKHYWYTSWPDHKTPDSAQPLLQLMLDVEEDRLASQGRGPVVVHCSAGIGRTGCFIATSIGCQQLKEEGVVDALSIVCQLRMDRGGMVQTSEQYEFVHHALCLYESRLSAETVQ