P21817 Q16314 Q16368 Q9NPK1 Q9P1U4 RYR1_HUMAN Ryanodine receptor 1 RYR-1 RyR1 Skeletal muscle calcium release channel Skeletal muscle ryanodine receptor Skeletal muscle-type ryanodine receptor Type 1 ryanodine receptor RYR1 RYDR Homo sapiens Human Eukaryota Metazoa Chordata Craniata Vertebrata Euteleostomi Mammalia Eutheria Euarchontoglires Primates Haplorrhini Catarrhini Hominidae Homo NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2) PARTIAL PROTEIN SEQUENCE Skeletal muscle SEQUENCE REVISION TO 2324; 2840 AND 3380 INVOLVEMENT IN MHS1 VARIANTS MHS1 ARG-248 AND CYS-471 VARIANTS LEU-1787; CYS-2060 AND VAL-2550 Muscle SEQUENCE REVISION TO 1365-1368 VARIANT CMYO1A HIS-2435 ALTERNATIVE SPLICING Muscle NUCLEOTIDE SEQUENCE [GENOMIC DNA] ALTERNATIVE SPLICING VARIANTS ALA-1832 AND VAL-2550 NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 598-722 Skeletal muscle NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 603-641 VARIANT MHS1 CYS-614 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 603-627 VARIANT MHS1 CYS-614 NUCLEOTIDE SEQUENCE [MRNA] OF 4696-4974 SUBCELLULAR LOCATION Myometrium TISSUE SPECIFICITY INTERACTION WITH CALM AND S100A1 FUNCTION TRANSPORTER ACTIVITY ACTIVITY REGULATION INVOLVEMENT IN KDS VARIANT KDS GLU-33 FUNCTION TRANSPORTER ACTIVITY ACTIVITY REGULATION PHOSPHORYLATION AT SER-2843 S-NITROSYLATION IDENTIFICATION IN A COMPLEX WITH PDE4D; PKA; FKBP1A AND PROTEIN PHOSPHATASE 1 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-4864 AND SER-4867 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS] Liver REVIEW INVOLVEMENT IN KDS VARIANTS KDS ARG-2206; TRP-2452 AND PHE-2776 INVOLVEMENT IN SAMARITAN MYOPATHY VARIANT CYS-1088 INVOLVEMENT IN KDS VARIANT KDS CYS-2508 VARIANTS CMYO1A CYS-163 AND MET-403 VARIANTS MHS1 CYS-163 AND MET-403 VARIANT CMYO1A SER-522 VARIANT MHS1 ARG-341 VARIANT MHS1 ARG-2434 VARIANT MHS1 ARG-2434 VARIANT MHS1 ARG-35 VARIANT MHS1 LEU-614 VARIANT MHS1 TRP-552 VARIANTS MHS1 CYS-2163; MET-2168 AND MET-2206 VARIANT CMYO1A HIS-2163 VARIANTS MHS1 CYS-2458 AND HIS-2458 VARIANTS MHS1 HIS-533 AND ARG-2206 VARIANTS MHS1 LEU-2435 AND HIS-2454 VARIANT CMYO1A THR-4898 CHARACTERIZATION OF VARIANT CMYO1A THR-4898 VARIANTS MHS1 TRP-2452 AND HIS-2454 VARIANT MHS1 ILE-4826 VARIANT MHS1 CYS-2454 VARIANT CMYO1A ALA-4637 VARIANT MHS1 GLU-2347 DEL VARIANTS MHS1 CYS-163; ARG-248; CYS-614; MET-2168; MET-2206; ILE-2214; THR-2367; ASN-2431; ARG-2434 AND HIS-2454 VARIANTS CMYO1A MET-2168; 4214-ARG--PHE-4216 DEL; 4647-LEU-SER-4648 DEL; PRO-4793; CYS-4796; CYS-4825; PHE-4860 DEL; HIS-4861; TRP-4893; THR-4898; GLU-4899 AND GLY-4914 VARIANTS CMYO1A HIS-4861; ARG-4891; THR-4898; ARG-4899 AND VAL-4906 CHARACTERIZATION OF VARIANTS CMYO1A MET-2168; HIS-4861; TRP-4893; THR-4898 AND ARG-4899 FUNCTION TRANSPORTER ACTIVITY VARIANT MHS1 GLU-2129 VARIANT MHS1 THR-2350 CHARACTERIZATION OF VARIANT MHS1 THR-2350 VARIANTS MHS1 CYS-163; ASN-166; ARG-341; HIS-401; CYS-614; GLU-2129; MET-2168; MET-2206; THR-2428; ARG-2434; HIS-2435; TRP-2452 AND HIS-2454 VARIANTS MHS1 CYS-163; ARG-341; CYS-614; CYS-2454; MET-3916 AND LEU-4973 VARIANT CMYO1B SER-3527 VARIANT MHS1 CYS-401 VARIANTS MHS1 CYS-163; CYS-401; HIS-2163; MET-2206; ILE-2280; ARG-2434; LEU-2435; CYS-2458; SER-4136; LEU-4234; TRP-4737; VAL-4942 AND LEU-4973 VARIANT MHS1 CYS-2355 VARIANTS MHS1 SER-4668 AND VAL-4838 VARIANTS ALA-1832 AND GLU-3756 VARIANT CMYO1B ILE-4849 VARIANT MHS1 TRP-328 CHARACTERIZATION OF VARIANT MHS1 TRP-328 VARIANTS CMYO1A HIS-4861; CYS-4864; TRP-4893 AND THR-4940 VARIANTS CMYO1A CYS-614 AND GLU-4899 VARIANTS CMYO1B GLU-215; PRO-4650 AND GLN-4724 VARIANTS MHS1 CYS-44; CYS-533; LYS-2101; LEU-2117; PRO-2163; MET-2168; LEU-2435 AND HIS-2454 VARIANTS MHS1 PHE-2182 AND ALA-2375 VARIANT CMYO1A 4863-ARG--ASP-4869 DELINS TYR INVOLVEMENT IN CMYO1B VARIANT CORE/ROD DISEASE ILE-4637 VARIANTS CMYO1A ASP-4638; PRO-4651; CYS-4861; HIS-4861; GLN-4893; THR-4898; GLY-4914; THR-4914; 4927-VAL-ILE-4928 DEL AND THR-4940 VARIANTS MHS1 CYS-163; ARG-248; CYS-614; CYS-2163; MET-2168; MET-2206; ILE-2214; THR-2350; THR-2367; ASN-2431; ARG-2434; VAL-2437; HIS-2454 AND PRO-4824 VARIANTS MHS1 TRP-2676 AND SER-2787 VARIANTS CMYO1A GLY-160; ASP-4638; PHE-4814; HIS-4861 AND MET-4938 VARIANTS MHS1 CYS-614; MET-2346; GLY-2348; TRP-2452; HIS-2458; PRO-4824 AND GLU-4939 VARIANT MHS1 SER-2342 VARIANTS MHS1 ARG-35; CYS-163; LEU-163; ARG-165; ASN-166; CYS-177; CYS-178; VAL-227; ARG-248; TRP-328; ARG-341; SER-401; HIS-401; MET-403; SER-522; TRP-552; CYS-614; LEU-614; CYS-2163; HIS-2163; MET-2168; MET-2206; ARG-2206; ASP-2344; MET-2346; THR-2350; THR-2428; ARG-2434; HIS-2435; CYS-2454; HIS-2454; CYS-2458; TRP-2676; SER-2787; MET-3916; SER-4684; GLN-4737; TRP-4737; ILE-4826; VAL-4838; ILE-4849; ARG-4876; GLU-4939 AND LEU-4973 CHARACTERIZATION OF VARIANTS MHS1 LEU-163; MET-2206; THR-2428; CYS-2454 AND HIS-2454 FUNCTION TRANSPORTER ACTIVITY ACTIVITY REGULATION VARIANTS CMYO1B TRP-109 AND LYS-2423 VARIANTS VAL-485 AND CYS-2060 VARIANT CMYO1A VAL-4846 VARIANTS CMYO1A CYS-4861; HIS-4861; VAL-4897 AND THR-4914 VARIANTS CMYO1B GLN-4558; VAL-4846 AND ILE-4849 VARIANT CMYO1A MET-4882 VARIANTS CMYO1B VAL-13; SER-1704; PRO-2421; LYS-2423; HIS-3539; GLN-3772; GLN-4558; MET-4842 AND ILE-4849 VARIANTS MHS1 ARG-13; LYS-226; LEU-367; HIS-530; TYR-544; CYS-1043; GLY-1352; LEU-1787; HIS-2336; LYS-2404; TRP-2676; GLY-2730; SER-2787; LYS-2880; PRO-3217; LYS-3290; TRP-3772; ARG-3806; LEU-4501; VAL-4838; ARG-4876 AND THR-4938 VARIANTS GLY-1342; ALA-1832; CYS-2060; VAL-2321; VAL-2550; GLN-3583 AND GLU-3756 VARIANT MHS1 CYS-2508 VARIANTS MHS1 ASN-382; LYS-1058; ARG-1393 AND HIS-1679 VARIANT CMYO1A GLY-2508 VARIANTS CMYO1B THR-402; LEU-2035; LYS-3326 AND GLY-3402 VARIANTS MHS1 ASN-1056; HIS-1127; ARG-1467; VAL-1571; GLN-2013; CYS-2248; GLY-2400; GLY-2593; TYR-2976; GLN-3410; TYR-3501 AND CYS-3933 VARIANTS LYS-899; CYS-2060 AND GLN-3360 VARIANTS CMYO1A GLY-160; GLN-2204; HIS-3366; CYS-3933 AND ASP-4743 VARIANTS LEU-1787; CYS-2060 AND ALA-4493 VARIANTS MHS1 HIS-1056; MET-2627 AND LEU-4234 VARIANTS MHS1 ALA-40; CYS-163; ARG-248; ARG-341; PRO-487; ALA-518; CYS-614; HIS-1043; LEU-1787; HIS-2163; MET-2206; HIS-2248; HIS-2351; MET-2354; LEU-2358; GLN-2383; ARG-2434; HIS-2454; ARG-3711; VAL-4178; ARG-4230; GLU-4837; HIS-4861 AND GLY-4906 VARIANTS CMYO1A TRP-975; MET-2168 AND GLY-3238 VARIANTS MET-974; LEU-1109; ARG-1393; CYS-2060 AND VAL-2321 VARIANTS CMYO1A HIS-4861; ALA-4897 AND THR-4898 CHARACTERIZATION OF VARIANT CMYO1A GLY-2508 CHARACTERIZATION OF VARIANT MHS1 HIS-2508 MUTAGENESIS OF ARG-2508 CHARACTERIZATION OF VARIANTS MHS1 ARG-35; CYS-163; LEU-163; ARG-248; ARG-341; CYS-401; HIS-401; SER-522; CYS-614 AND LEU-614 MUTAGENESIS OF TYR-522 CHARACTERIZATION OF VARIANTS MHS1 CYS-2163; HIS-2163; MET-2168; MET-2206; THR-2350; ALA-2375; ARG-2434; HIS-2435; CYS-2454; HIS-2454; CYS-2458; HIS-2458 AND HIS-2508 CHARACTERIZATION OF VARIANT CMYO1A CYS-2508 FUNCTION TRANSPORTER ACTIVITY VARIANT MHS1 TRP-4737 CHARACTERIZATION OF VARIANT MHS1 TRP-4737 VARIANT ARG-705 VARIANTS CMYO1A PRO-2963 AND ASP-4806 Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules (PubMed:11741831, PubMed:16163667, PubMed:18268335, PubMed:18650434, PubMed:26115329). Repeated very high-level exercise increases the open probability of the channel and leads to Ca(2+) leaking into the cytoplasm (PubMed:18268335). Can also mediate the release of Ca(2+) from intracellular stores in neurons, and may thereby promote prolonged Ca(2+) signaling in the brain. Required for normal embryonic development of muscle fibers and skeletal muscle. Required for normal heart morphogenesis, skin development and ossification during embryogenesis (By similarity). Ca(2+)(in) = Ca(2+)(out) The calcium release is activated by increased cytosolic calcium levels, by nitric oxyde (NO), caffeine and ATP (PubMed:16163667, PubMed:18268335). Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity (By similarity). Channel activity is regulated by calmodulin (CALM) (PubMed:18650434). Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites (By similarity). Homotetramer. Can also form heterotetramers with RYR2 (By similarity). Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (PubMed:18268335). Repeated very high-level exercise decreases interaction with PDE4D and protein phosphatase 1 (PP1) (PubMed:18268335). Interacts with CALM; CALM with bound calcium inhibits the RYR1 channel activity (PubMed:18650434). Interacts with S100A1 (PubMed:18650434). Interacts with FKBP1A; this stabilizes the closed conformation of the channel. Interacts with CACNA1S; interaction with CACNA1S is important for activation of the RYR1 channel. Interacts with CACNB1. Interacts with TRDN and ASPH; these interactions stimulate RYR1 channel activity. Interacts with SELENON (By similarity). Interacts with scorpion calcins (AC P0DPT1; AC P0DM30; AC A0A1L4BJ42; AC P59868; AC P60254; AC B8QG00; AC L0GBR1; AC P60252; AC P60253) (By similarity). Sarcoplasmic reticulum membrane Multi-pass membrane protein The number of predicted transmembrane domains varies between orthologs. Both N-terminus and C-terminus are cytoplasmic. P21817-1 1 P21817-2 2 P21817-3 3 Experimental confirmation may be lacking for some isoforms. Skeletal muscle and brain (cerebellum and hippocampus). The calcium release channel activity resides in the C-terminal region while the remaining part of the protein constitutes the 'foot' structure spanning the junctional gap between the sarcoplasmic reticulum (SR) and the T-tubule. Pore opening is mediated via the cytoplasmic calcium-binding domains that mediate a small rotation of the channel-forming transmembrane regions that then leads to channel opening. Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2843 may increase channel activity. Repeated very high-level exercise increases phosphorylation at Ser-2843. Activated by reversible S-nitrosylation (By similarity). Repeated very high-level exercise increases S-nitrosylation (PubMed:18268335). Malignant hyperthermia 1 MHS1 Autosomal dominant pharmacogenetic disorder of skeletal muscle and is one of the main causes of death due to anesthesia. In susceptible people, an MH episode can be triggered by all commonly used inhalational anesthetics such as halothane and by depolarizing muscle relaxants such as succinylcholine. The clinical features of the myopathy are hyperthermia, accelerated muscle metabolism, contractures, metabolic acidosis, tachycardia and death, if not treated with the postsynaptic muscle relaxant, dantrolene. Susceptibility to MH can be determined with the 'in vitro' contracture test (IVCT): observing the magnitude of contractures induced in strips of muscle tissue by caffeine alone and halothane alone. Patients with normal response are MH normal (MHN), those with abnormal response to caffeine alone or halothane alone are MH equivocal (MHE(C) and MHE(H) respectively). Disease susceptibility is associated with variants affecting the gene represented in this entry. Congenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia CMYO1A An autosomal dominant myopathy characterized by hypotonia and proximal muscle weakness primarily affecting the lower limbs, beginning in infancy or early childhood. Some patients manifest later onset of symptoms. The clinical course of the disorder is usually slow or non-progressive in adulthood, and the severity of the symptoms is variable. Affected individuals typically show delayed motor development and usually achieve independent walking, although many have difficulty running or climbing stairs. Additional features often include mild facial weakness, joint laxity, shoulder girdle weakness, and skeletal manifestations, such as dislocation of the hips, foot deformities, scoliosis, and Achilles tendon contractures. Microscopic examination of affected skeletal muscle reveals a predominance of type I fibers containing amorphous-looking areas (cores) that do not stain with oxidative and phosphorylase histochemical techniques. Additional pathologic findings may also be observed on muscle biopsy. CMYO1A affected individuals are at risk for malignant hyperthermia, and both disorders may be present in the same family. The disease is caused by variants affecting the gene represented in this entry. Congenital myopathy 1B, autosomal recessive CMYO1B An autosomal recessive myopathy characterized by severe hypotonia and generalized muscle weakness and atrophy apparent soon after birth or in early childhood. Affected individuals show delayed motor development, proximal muscle weakness with axial and shoulder girdle involvement, difficulty walking or running, external ophthalmoplegia, and bulbar weakness often resulting in feeding difficulties and respiratory insufficiency. Disease severity is variable. Some affected individuals show symptoms in utero, including reduced fetal movements, polyhydramnios, and intrauterine growth restriction. Some patients have lethal fetal akinesia with death in utero. Muscle biopsy can show variable findings, including multiple and poorly circumscribed areas of sarcomere disorganization and mitochondria depletion (areas termed minicores). Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present. The disease is caused by variants affecting the gene represented in this entry. Defects in RYR1 may be a cause of Samaritan myopathy, a congenital myopathy with benign course. Patients display severe hypotonia and respiratory distress at birth. Unlike other congenital myopathies, the health status constantly improves and patients are minimally affected at adulthood. King-Denborough syndrome KDS An autosomal dominant disorder characterized by the triad of dysmorphic features, congenital myopathy, and susceptibility to malignant hyperthermia. Variable expressivity has been reported in several cases. The disease is caused by variants affecting the gene represented in this entry. Coexpression of normal and mutant Thr-4898 RYR1 in a 1:1 ratio produces RYR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca(2+) release are reduced by 67%. Binding of [3H]ryanodine indicates that the heterozygous channel is activated by Ca(2+) concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells shows a significantly increased resting cytoplasmic Ca(2+) level and a significantly reduced luminal Ca(2+) level. These data indicated a leaky channel, possibly caused by a reduction in the Ca(2+) concentration required for channel activation. Comparison with 2 other coexpressed mutant/normal channels suggests that the Thr-4898 mutation produces one of the most abnormal RYR1 channels that has been investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected CCD individuals. Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR1 subfamily. Ryanodine receptor entry RYR1 entry Leiden Open Variation Database (LOVD) 3D-structure Alternative splicing ATP-binding Calcium Calcium channel Calcium transport Calmodulin-binding Developmental protein Direct protein sequencing Disease variant Ion channel Ion transport Ligand-gated ion channel Membrane Metal-binding Nucleotide-binding Phosphoprotein Proteomics identification Receptor Reference proteome Repeat S-nitrosylation Sarcoplasmic reticulum Transmembrane Transmembrane helix Transport Ca(2+) Ca(2+) ATP caffeine ATP ATP Ca(2+) L R L V K E C R G A R C R W E G R C R L G R D N R C Y C G E M K D V G R A T R W G R R L H N R C R H R S M T I M R C M V L P V A Y S R H R C R H D Y R W R C R L G R N K V M R W R C R H D H D N E K Y C R K R L R H S G A G K R K R S N I V R H G S P L G A K Q H L G C M K V L D E R C R H R P V M I F H Q T M T R V I R C R H V I I V R H N S E D V M E G A T N H V M R C I L A T G A A Q D G E K A P M K A T D N G R R H R L A V R W R C R H R C R H R C R G R H V I L V R G V M R W D G S F E K T S E K L P H Y A V S P E G E K N K P Q R H C G P Q D Y P S R H E Q T R Q E R Q R W G R I M Y C R S G V M R V L P A P L R Q T A T I G D L P H P P S F S K Q R Q R W G D L P Y C N D L F L P R C T I Q E L V V M A V V I R C R H FYNKSED Y Y C K R T M G R R Q R W G A G V I T G E G R A G A V R G R T I M I T D E A T G V P L Y C R K R S GEAQ RGA N K R A R A MGDAEGEDEVQFLRTDDEVVLQCSATVLKEQLKLCLAAEGFGNRLCFLEPTSNAQNVPPDLAICCFVLEQSLSVRALQEMLANTVEAGVESSQGGGHRTLLYGHAILLRHAHSRMYLSCLTTSRSMTDKLAFDVGLQEDATGEACWWTMHPASKQRSEGEKVRVGDDIILVSVSSERYLHLSTASGELQVDASFMQTLWNMNPICSRCEEGFVTGGHVLRLFHGHMDECLTISPADSDDQRRLVYYEGGAVCTHARSLWRLEPLRISWSGSHLRWGQPLRVRHVTTGQYLALTEDQGLVVVDASKAHTKATSFCFRISKEKLDVAPKRDVEGMGPPEIKYGESLCFVQHVASGLWLTYAAPDPKALRLGVLKKKAMLHQEGHMDDALSLTRCQQEESQAARMIHSTNGLYNQFIKSLDSFSGKPRGSGPPAGTALPIEGVILSLQDLIIYFEPPSEDLQHEEKQSKLRSLRNRQSLFQEEGMLSMVLNCIDRLNVYTTAAHFAEFAGEEAAESWKEIVNLLYELLASLIRGNRSNCALFSTNLDWLVSKLDRLEASSGILEVLYCVLIESPEVLNIIQENHIKSIISLLDKHGRNHKVLDVLCSLCVCNGVAVRSNQDLITENLLPGRELLLQTNLINYVTSIRPNIFVGRAEGTTQYSKWYFEVMVDEVTPFLTAQATHLRVGWALTEGYTPYPGAGEGWGGNGVGDDLYSYGFDGLHLWTGHVARPVTSPGQHLLAPEDVISCCLDLSVPSISFRINGCPVQGVFESFNLDGLFFPVVSFSAGVKVRFLLGGRHGEFKFLPPPGYAPCHEAVLPRERLHLEPIKEYRREGPRGPHLVGPSRCLSHTDFVPCPVDTVQIVLPPHLERIREKLAENIHELWALTRIEQGWTYGPVRDDNKRLHPCLVDFHSLPEPERNYNLQMSGETLKTLLALGCHVGMADEKAEDNLKKTKLPKTYMMSNGYKPAPLDLSHVRLTPAQTTLVDRLAENGHNVWARDRVGQGWSYSAVQDIPARRNPRLVPYRLLDEATKRSNRDSLCQAVRTLLGYGYNIEPPDQEPSQVENQSRCDRVRIFRAEKSYTVQSGRWYFEFEAVTTGEMRVGWARPELRPDVELGADELAYVFNGHRGQRWHLGSEPFGRPWQPGDVVGCMIDLTENTIIFTLNGEVLMSDSGSETAFREIEIGDGFLPVCSLGPGQVGHLNLGQDVSSLRFFAICGLQEGFEPFAINMQRPVTTWFSKGLPQFEPVPLEHPHYEVSRVDGTVDTPPCLRLTHRTWGSQNSLVEMLFLRLSLPVQFHQHFRCTAGATPLAPPGLQPPAEDEARAAEPDPDYENLRRSAGGWSEAENGKEGTAKEGAPGGTPQAGGEAQPARAENEKDATTEKNKKRGFLFKAKKVAMMTQPPATPTLPRLPHDVVPADNRDDPEIILNTTTYYYSVRVFAGQEPSCVWAGWVTPDYHQHDMSFDLSKVRVVTVTMGDEQGNVHSSLKCSNCYMVWGGDFVSPGQQGRISHTDLVIGCLVDLATGLMTFTANGKESNTFFQVEPNTKLFPAVFVLPTHQNVIQFELGKQKNIMPLSAAMFQSERKNPAPQCPPRLEMQMLMPVSWSRMPNHFLQVETRRAGERLGWAVQCQEPLTMMALHIPEENRCMDILELSERLDLQRFHSHTLRLYRAVCALGNNRVAHALCSHVDQAQLLHALEDAHLPGPLRAGYYDLLISIHLESACRSRRSMLSEYIVPLTPETRAITLFPPGRSTENGHPRHGLPGVGVTTSLRPPHHFSPPCFVAALPAAGAAEAPARLSPAIPLEALRDKALRMLGEAVRDGGQHARDPVGGSVEFQFVPVLKLVSTLLVMGIFGDEDVKQILKMIEPEVFTEEEEEEDEEEEGEEEDEEEKEEDEEETAQEKEDEEKEEEEAAEGEKEEGLEEGLLQMKLPESVKLQMCHLLEYFCDQELQHRVESLAAFAERYVDKLQANQRSRYGLLIKAFSMTAAETARRTREFRSPPQEQINMLLQFKDGTDEEDCPLPEEIRQDLLDFHQDLLAHCGIQLDGEEEEPEEETTLGSRLMSLLEKVRLVKKKEEKPEEERSAEESKPRSLQELVSHMVVRWAQEDFVQSPELVRAMFSLLHRQYDGLGELLRALPRAYTISPSSVEDTMSLLECLGQIRSLLIVQMGPQEENLMIQSIGNIMNNKVFYQHPNLMRALGMHETVMEVMVNVLGGGESKEIRFPKMVTSCCRFLCYFCRISRQNQRSMFDHLSYLLENSGIGLGMQGSTPLDVAAASVIDNNELALALQEQDLEKVVSYLAGCGLQSCPMLVAKGYPDIGWNPCGGERYLDFLRFAVFVNGESVEENANVVVRLLIRKPECFGPALRGEGGSGLLAAIEEAIRISEDPARDGPGIRRDRRREHFGEEPPEENRVHLGHAIMSFYAALIDLLGRCAPEMHLIQAGKGEALRIRAILRSLVPLEDLVGIISLPLQIPTLGKDGALVQPKMSASFVPDHKASMVLFLDRVYGIENQDFLLHVLDVGFLPDMRAAASLDTATFSTTEMALALNRYLCLAVLPLITKCAPLFAGTEHRAIMVDSMLHTVYRLSRGRSLTKAQRDVIEDCLMSLCRYIRPSMLQHLLRRLVFDVPILNEFAKMPLKLLTNHYERCWKYYCLPTGWANFGVTSEEELHLTRKLFWGIFDSLAHKKYDPELYRMAMPCLCAIAGALPPDYVDASYSSKAEKKATVDAEGNFDPRPVETLNVIIPEKLDSFINKFAEYTHEKWAFDKIQNNWSYGENIDEELKTHPMLRPYKTFSEKDKEIYRWPIKESLKAMIAWEWTIEKAREGEEEKTEKKKTRKISQSAQTYDPREGYNPQPPDLSAVTLSRELQAMAEQLAENYHNTWGRKKKQELEAKGGGTHPLLVPYDTLTAKEKARDREKAQELLKFLQMNGYAVTRGLKDMELDSSSIEKRFAFGFLQQLLRWMDISQEFIAHLEAVVSSGRVEKSPHEQEIKFFAKILLPLINQYFTNHCLYFLSTPAKVLGSGGHASNKEKEMITSLFCKLAALVRHRVSLFGTDAPAVVNCLHILARSLDARTVMKSGPEIVKAGLRSFFESASEDIEKMVENLRLGKVSQARTQVKGVGQNLTYTTVALLPVLTTLFQHIAQHQFGDDVILDDVQVSCYRTLCSIYSLGTTKNTYVEKLRPALGECLARLAAAMPVAFLEPQLNEYNACSVYTTKSPRERAILGLPNSVEEMCPDIPVLERLMADIGGLAESGARYTEMPHVIEITLPMLCSYLPRWWERGPEAPPSALPAGAPPPCTAVTSDHLNSLLGNILRIIVNNLGIDEASWMKRLAVFAQPIVSRARPELLQSHFIPTIGRLRKRAGKVVSEEEQLRLEAKAEAQEGELLVRDEFSVLCRDLYALYPLLIRYVDNNRAQWLTEPNPSAEELFRMVGEIFIYWSKSHNFKREEQNFVVQNEINNMSFLTADNKSKMAKAGDIQSGGSDQERTKKKRRGDRYSVQTSLIVATLKKMLPIGLNMCAPTDQDLITLAKTRYALKDTDEEVREFLHNNLHLQGKVEGSPSLRWQMALYRGVPGREEDADDPEKIVRRVQEVSAVLYYLDQTEHPYKSKKAVWHKLLSKQRRRAVVACFRMTPLYNLPTHRACNMFLESYKAAWILTEDHSFEDRMIDDLSKAGEQEEEEEEVEEKKPDPLHQLVLHFSRTALTEKSKLDEDYLYMAYADIMAKSCHLEEGGENGEAEEEVEVSFEEKQMEKQRLLYQQARLHTRGAAEMVLQMISACKGETGAMVSSTLKLGISILNGGNAEVQQKMLDYLKDKKEVGFFQSIQALMQTCSVLDLNAFERQNKAEGLGMVNEDGTVINRQNGEKVMADDEFTQDLFRFLQLLCEGHNNDFQNYLRTQTGNTTTINIIICTVDYLLRLQESISDFYWYYSGKDVIEEQGKRNFSKAMSVAKQVFNSLTEYIQGPCTGNQQSLAHSRLWDAVVGFLHVFAHMMMKLAQDSSQIELLKELLDLQKDMVVMLLSLLEGNVVNGMIARQMVDMLVESSSNVEMILKFFDMFLKLKDIVGSEAFQDYVTDPRGLISKKDFQKAMDSQKQFSGPEIQFLLSCSEADENEMINCEEFANRFQEPARDIGFNVAVLLTNLSEHVPHDPRLHNFLELAESILEYFRPYLGRIEIMGASRRIERIYFEISETNRAQWEMPQVKESKRQFIFDVVNEGGEAEKMELFVSFCEDTIFEMQIAAQISEPEGEPETDEDEGAGAAEAGAEGAEEGAAGLEGTAATAAAGATARVVAAAGRALRGLSYRSLRRRVRRLRRLTAREAATAVAALLWAAVTRAGAAGAGAAAGALGLLWGSLFGGGLVEGAKKVTVTELLAGMPDPTSDEVHGEQPAGPGGDADGEGASEGAGDAAEGAGDEEEAVHEAGPGGADGAVAVTDGGPFRPEGAGGLGDMGDTTPAEPPTPEGSPILKRKLGVDGVEEELPPEPEPEPEPELEPEKADAENGEKEEVPEPTPEPPKKQAPPSPPPKKEEAGGEFWGELEVQRVKFLNYLSRNFYTLRFLALFLAFAINFILLFYKVSDSPPGEDDMEGSAAGDVSGAGSGGSSGWGLGAGEEAEGDEDENMVYYFLEESTGYMEPALRCLSLLHTLVAFLCIIGYNCLKVPLVIFKREKELARKLEFDGLYITEQPEDDDVKGQWDRLVLNTPSFPSNYWDKFVKRKVLDKHGDIYGRERIAELLGMDLATLEITAHNERKPNPPPGLLTWLMSIDVKYQIWKFGVIFTDNSFLYLGWYMVMSLLGHYNNFFFAAHLLDIAMGVKTLRTILSSVTHNGKQLVMTVGLLAVVVYLYTVVAFNFFRKFYNKSEDEDEPDMKCDDMMTCYLFHMYVGVRAGGGIGDEIEDPAGDEYELYRVVFDITFFFFVIVILLAIIQGLIIDAFGELRDQQEQVKEDMETKCFICGIGSDYFDTTPHGFETHTLEEHNLANYMFFLMYLINKDETEHTGQESYVWKMYQERCWDFFPAGDCFRKQYEDQLS 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