301:), and can share few to no exons with the canonical sequence. In addition, they can have different biological effects—for example, in an extreme case, the function of one isoform can promote cell survival, while another promotes cell death—or can have similar basic functions but differ in their sub-cellular localization. A 2016 study, however, functionally characterized all the isoforms of 1,492 genes and determined that most isoforms behave as "functional alloforms." The authors came to the conclusion that isoforms behave like distinct proteins after observing that the functional of most isoforms did not overlap. Because the study was conducted on cells
31:
197:
270:
protein isoforms. Although ~95% of multi-exonic genes are thought to be alternatively spliced, one study on noisy splicing observed that most of the different low-abundance transcripts are noise, and predicts that most alternative transcript and protein isoforms present in a cell are not functionally relevant.
265:
experiments using gel electrophoresis and mass spectrometry have demonstrated that the correlation between transcript and protein counts is often low, and that one protein isoform is usually dominant. One 2015 study states that the cause of this discrepancy likely occurs after translation, though the
125:
of mRNA, though it is not clear to what extent such a process affects the diversity of the human proteome, as the abundance of mRNA transcript isoforms does not necessarily correlate with the abundance of protein isoforms. Three-dimensional protein structure comparisons can be used to help determine
269:
Alternative splicing generally describes a tightly regulated process in which alternative transcripts are intentionally generated by the splicing machinery. However, such transcripts are also produced by splicing errors in a process called "noisy splicing," and are also potentially translated into
134:. The specificity of translated isoforms is derived by the protein's structure/function, as well as the cell type and developmental stage during which they are produced. Determining specificity becomes more complicated when a protein has multiple subunits and each subunit has multiple isoforms.
297:—or functionally analogous—sequences in other species. Isoforms are assumed to have similar functional properties, as most have similar sequences, and share some to most exons with the canonical sequence. However, some isoforms show much greater divergence (for example, through
305:, it is not known if the isoforms in the expressed human proteome share these characteristics. Additionally, because the function of each isoform must generally be determined separately, most identified and predicted isoforms still have unknown functions.
266:
mechanism is essentially unknown. Consequently, although alternative splicing has been implicated as an important link between variation and disease, there is no conclusive evidence that it acts primarily by producing novel protein isoforms.
436:
G6PDA: normal ratio of active isoforms in cells of any tissue is 1:1 shared with G6PDG. This is precisely the normal isoform ratio in hyperplasia. Only one of these isoforms is found during neoplasia.
58:
or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have unique functions. A set of protein isoforms may be formed from
433:, an enzyme superfamily responsible for the detoxification pathway of many drugs, environmental pollutants, and toxic endogenous compounds has 16 known isoforms encoded in the human genome.
273:
Other transcriptional and post-transcriptional regulatory steps can also produce different protein isoforms. Variable promoter usage occurs when the transcriptional machinery of a cell (
261:
have been used to identify alternatively spliced transcripts and measure their abundances. Transcript abundance is often used as a proxy for the abundance of protein isoforms, though
285:) begin transcription at different promoters—the region of DNA near a gene that serves as an initial binding site—resulting in slightly modified transcripts and protein isoforms.
113:) can be identified in humans. Isoforms at the protein level can manifest in the deletion of whole domains or shorter loops, usually located on the surface of the protein.
644:
Breitbart RE, Andreadis A, Nadal-Ginard B (1987-01-01). "Alternative splicing: a ubiquitous mechanism for the generation of multiple protein isoforms from single genes".
838:
Kornblihtt AR, Schor IE, Alló M, Dujardin G, Petrillo E, Muñoz MJ (March 2013). "Alternative splicing: a pivotal step between eukaryotic transcription and translation".
730:
Sommer, Markus J.; Cha, Sooyoung; Varabyou, Ales; Rincon, Natalia; Park, Sukhwan; Minkin, Ilia; Pertea, Mihaela; Steinegger, Martin; Salzberg, Steven L. (2022-12-15).
604:
Andreadis A, Gallego ME, Nadal-Ginard B (1987-01-01). "Generation of protein isoform diversity by alternative splicing: mechanistic and biological implications".
207:
The primary mechanisms that produce protein isoforms are alternative splicing and variable promoter usage, though modifications due to genetic changes, such as
1293:"Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7. Identification of a critical aromatic amino acid residue at position 33"
360:. Glycoforms may be detected through detailed chemical analysis of separated glycoforms, but more conveniently detected through differential reaction with
90:) of a gene, or even different parts of exons from RNA to form different mRNA sequences. Each unique sequence produces a specific form of a protein.
1343:
126:
which, if any, isoforms represent functional protein products, and the structure of most isoforms in the human proteome has been predicted by
121:
One single gene has the ability to produce multiple proteins that differ both in structure and composition; this process is regulated by the
97:
and the large diversity of proteins seen in an organism: different proteins encoded by the same gene could increase the diversity of the
93:
The discovery of isoforms could explain the discrepancy between the small number of protein coding regions of genes revealed by the
1375:
222:
process that produces mRNA transcript isoforms, and is a major molecular mechanism that may contribute to protein diversity. The
1143:"Revisiting the identification of canonical splice isoforms through integration of functional genomics and proteomics evidence"
293:
Generally, one protein isoform is labeled as the canonical sequence based on criteria such as its prevalence and similarity to
585:
219:
67:
182:
In human skeletal muscle, the preferred form is α2β2γ1. But in the human liver, the most abundant form is α1β2γ1.
1403:
71:
1193:
Sundvall M, Veikkolainen V, Kurppa K, Salah Z, Tvorogov D, van Zoelen EJ, Aqeilan R, Elenius K (December 2010).
568:
Kozlowski, L.; Orlowski, J.; Bujnicki, J. M. (2012). "Structure
Prediction for Alternatively Spliced Proteins".
474:
Brett D, Pospisil H, Valcárcel J, Reich J, Bork P (January 2002). "Alternative splicing and genome complexity".
365:
254:
392:
1368:
231:
139:
443:, a family of enzymes that catalyze the oxidation of monoamines, exists in two isoforms, MAO-A and MAO-B.
1142:
430:
1550:
1242:
Yang X, Coulombe-Huntington J, Kang S, Sheynkman GM, Hao T, Richardson A, et al. (February 2016).
372:
1361:
427:, the enzyme responsible for the production of hyaluronan, has three isoforms in mammalian cells.
242:
17:
212:
110:
411:: despite its conserved nature, it has a varying number of isoforms (at least six in mammals).
1507:
418:
246:
328:
is an isoform of a protein that differs only with respect to the number or type of attached
1398:
357:
278:
191:
122:
106:
94:
59:
35:
908:
8:
424:
63:
657:
617:
1268:
1243:
1219:
1194:
1170:
1118:
1093:
1069:
1042:
1018:
993:
969:
944:
917:
892:
873:
812:
787:
758:
731:
545:
518:
499:
992:
Battle A, Khan Z, Wang SH, Mitrano A, Ford MJ, Pritchard JK, Gilad Y (February 2015).
1439:
1413:
1314:
1309:
1292:
1273:
1224:
1175:
1123:
1074:
1023:
974:
922:
865:
817:
763:
712:
661:
621:
581:
550:
491:
440:
294:
227:
102:
877:
336:
often consist of a number of different glycoforms, with alterations in the attached
1517:
1475:
1470:
1465:
1304:
1291:
Barre L, Fournel-Gigleux S, Finel M, Netter P, Magdalou J, Ouzzine M (March 2007).
1263:
1255:
1214:
1206:
1165:
1157:
1113:
1105:
1064:
1054:
1013:
1005:
964:
956:
912:
904:
855:
847:
807:
799:
753:
743:
702:
692:
653:
613:
573:
540:
530:
503:
483:
1244:"Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing"
143:(AMPK), an enzyme, which performs different roles in human cells, has 3 subunits:
1423:
1408:
1059:
414:
396:
341:
167:Îł, regulatory domain, has three isoforms: Îł1, Îł2, and Îł3 which are encoded from
1444:
1259:
960:
803:
707:
697:
680:
577:
417:, the presence of which in the blood can be used as an aid in the diagnosis of
376:
298:
274:
230:, is the molecular machine inside the nucleus responsible for RNA cleavage and
788:"Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer"
1544:
1502:
1497:
349:
333:
1210:
1009:
1348:
1318:
1277:
1228:
1179:
1161:
1127:
1078:
1027:
978:
926:
869:
821:
767:
716:
554:
535:
495:
452:
353:
345:
319:
201:
79:
30:
665:
625:
1522:
1512:
388:
384:
380:
223:
157:β, regulatory domain, has two isoforms: β1 and β2 which are encoded from
748:
147:α, catalytic domain, has two isoforms: α1 and α2 which are encoded from
1449:
1109:
994:"Genomic variation. Impact of regulatory variation from RNA to protein"
860:
337:
262:
196:
109:
isoforms. It has been estimated that ~100,000 expressed sequence tags (
75:
1527:
732:"Structure-guided isoform identification for the human transcriptome"
517:
SchlĂĽter H, Apweiler R, HolzhĂĽtter HG, Jungblut PR (September 2009).
375:. Typical examples of glycoproteins consisting of glycoforms are the
127:
1241:
851:
1480:
1418:
250:
208:
98:
51:
34:
Protein A, B and C are isoforms encoded from the same gene through
1195:"Cell death or survival promoted by alternative isoforms of ErbB4"
516:
487:
1490:
1485:
1384:
519:"Finding one's way in proteomics: a protein species nomenclature"
408:
361:
258:
945:"Alternative Splicing May Not Be the Key to Proteome Complexity"
681:"On the Dependency of Cellular Protein Levels on mRNA Abundance"
1290:
1192:
369:
329:
282:
235:
176:
172:
168:
162:
158:
152:
148:
643:
1043:"Noisy splicing drives mRNA isoform diversity in human cells"
86:
has the ability to select different protein-coding segments (
1041:
Pickrell JK, Pai AA, Gilad Y, Pritchard JK (December 2010).
893:"Mechanisms and Regulation of Alternative Pre-mRNA Splicing"
603:
1353:
837:
473:
87:
83:
55:
1094:"Proteoform: a single term describing protein complexity"
1040:
567:
131:
101:. Isoforms at the RNA level are readily characterized by
729:
249:, its primary effects have mainly been studied through
105:
transcript studies. Many human genes possess confirmed
991:
344:. These modifications may result from differences in
942:
1141:Li HD, Menon R, Omenn GS, Guan Y (December 2014).
241:Because splicing is a process that occurs between
943:Tress ML, Abascal F, Valencia A (February 2017).
678:
215:are sometimes also considered distinct isoforms.
1542:
1140:
27:Forms of a protein produced from different genes
785:
1369:
1091:
74:are generally not considered. (For that, see
1284:
391:. An unusual glycoform variation is seen in
1376:
1362:
679:Liu Y, Beyer A, Aebersold R (April 2016).
50:", is a member of a set of highly similar
1308:
1267:
1218:
1169:
1117:
1068:
1058:
1017:
968:
916:
859:
811:
757:
747:
706:
696:
544:
534:
234:, removing non-protein coding segments (
195:
29:
14:
1543:
890:
1357:
938:
936:
909:10.1146/annurev-biochem-060614-034316
840:Nature Reviews Molecular Cell Biology
393:neuronal cell adhesion molecule, NCAM
1092:Smith LM, Kelleher NL (March 2013).
833:
831:
786:Dasgupta B, Chhipa RR (March 2016).
781:
779:
777:
639:
637:
635:
599:
597:
469:
467:
658:10.1146/annurev.bi.56.070187.002343
618:10.1146/annurev.cb.03.110187.001231
308:
24:
1331:Pathoma, Fundamentals of Pathology
933:
884:
792:Trends in Pharmacological Sciences
288:
68:post-transcriptional modifications
25:
1562:
1337:
828:
774:
632:
594:
464:
220:post-transcriptional modification
218:Alternative splicing is the main
1310:10.1111/j.1742-4658.2007.05670.x
72:post-translational modifications
1404:Post-translational modification
1325:
1235:
1186:
1134:
1085:
1034:
985:
140:5' AMP-activated protein kinase
949:Trends in Biochemical Sciences
723:
672:
561:
510:
366:lectin affinity chromatography
13:
1:
1199:Molecular Biology of the Cell
897:Annual Review of Biochemistry
646:Annual Review of Biochemistry
606:Annual Review of Cell Biology
570:Alternative pre-mRNA Splicing
458:
116:
54:that originate from a single
1383:
1060:10.1371/journal.pgen.1001236
891:Lee Y, Rio DC (2015-01-01).
313:
185:
7:
1344:MeSH entry protein isoforms
446:
431:UDP-glucuronosyltransferase
402:
10:
1567:
1445:Protein structural domains
1260:10.1016/j.cell.2016.01.029
961:10.1016/j.tibs.2016.08.008
804:10.1016/j.tips.2015.11.007
698:10.1016/j.cell.2016.03.014
578:10.1002/9783527636778.ch54
352:, or due to the action of
317:
189:
1458:
1432:
1391:
523:Chemistry Central Journal
130:and publicly released at
373:affinity electrophoresis
253:techniques—for example,
200:Different mechanisms of
1211:10.1091/mbc.E10-04-0332
1010:10.1126/science.1260793
421:, exists in 3 isoforms.
1162:10.1002/pmic.201400170
536:10.1186/1752-153X-3-11
348:during the process of
204:
39:
1508:Photoreceptor protein
419:myocardial infarction
397:polysialic acids, PSA
279:transcription factors
199:
60:alternative splicings
33:
1399:Protein biosynthesis
358:glycosyltransferases
192:Alternative splicing
123:alternative splicing
107:alternative splicing
95:human genome project
36:alternative splicing
1349:Definitions Isoform
749:10.7554/eLife.82556
708:20.500.11850/116226
425:Hyaluronan synthase
1156:(23–24): 2709–18.
1110:10.1038/nmeth.2369
205:
70:of a single gene;
40:
1551:Protein structure
1538:
1537:
1440:Protein structure
1414:Protein targeting
441:Monoamine oxidase
228:ribonucleoprotein
137:For example, the
16:(Redirected from
1558:
1518:Phycobiliprotein
1476:Globular protein
1471:Membrane protein
1466:List of proteins
1378:
1371:
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1297:The FEBS Journal
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1053:(12): e1001236.
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309:Related concepts
66:usage, or other
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1498:Fibrous protein
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1424:Protein methods
1409:Protein folding
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1205:(23): 4275–86.
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1039:
1035:
1004:(6222): 664–7.
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852:10.1038/nrm3525
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572:. p. 582.
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476:Nature Genetics
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415:Creatine kinase
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342:oligosaccharide
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289:Characteristics
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48:protein variant
44:protein isoform
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1338:External links
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1303:(5): 1256–64.
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1098:Nature Methods
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609:
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569:
563:
526:
522:
512:
482:(1): 29–30.
479:
475:
453:Gene isoform
439:
354:glycosidases
346:biosynthesis
325:
323:
320:Glycoprotein
302:
292:
281:, and other
272:
268:
240:
217:
206:
202:RNA splicing
181:
138:
136:
120:
92:
82:mechanisms,
80:RNA splicing
47:
43:
41:
1523:Phytochrome
1513:Biliprotein
861:11336/21049
389:haptoglobin
385:antitrypsin
381:orosomucoid
295:orthologous
247:translation
224:spliceosome
78:.) Through
76:Proteoforms
62:, variable
1450:Proteasome
1433:Structures
1150:Proteomics
742:: e82556.
459:References
395:involving
338:saccharide
263:proteomics
255:microarray
226:, a large
132:isoform.io
117:Definition
1528:Lipocalin
1392:Processes
326:glycoform
314:Glycoform
209:mutations
186:Mechanism
128:AlphaFold
1545:Category
1481:Globulin
1419:Proteome
1385:Proteins
1319:17263731
1278:26871637
1229:20943952
1180:25265570
1128:23443629
1079:21151575
1028:25657249
979:27712956
927:25784052
878:54560052
870:23385723
822:26711141
768:36519529
717:27104977
555:19740416
496:11743582
447:See also
403:Examples
364:, as in
303:in vitro
251:genomics
232:ligation
99:proteome
64:promoter
52:proteins
1491:Albumin
1486:Edestin
1269:4882190
1220:2993754
1171:4372202
1119:4114032
1070:3000347
1019:4507520
998:Science
970:6526280
918:4526142
813:4764394
759:9812405
666:3304142
626:2891362
546:2758878
504:2724843
409:G-actin
362:lectins
283:enzymes
236:introns
18:Isoform
1317:
1276:
1266:
1227:
1217:
1178:
1168:
1126:
1116:
1077:
1067:
1026:
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584:
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502:
494:
387:, and
370:lectin
330:glycan
177:PRKAG3
175:, and
173:PRKAG2
169:PRKAG1
163:PRKAB2
159:PRKAB1
153:PRKAA2
149:PRKAA1
46:, or "
1459:Types
1146:(PDF)
874:S2CID
736:eLife
500:S2CID
88:exons
1315:PMID
1274:PMID
1248:Cell
1225:PMID
1176:PMID
1124:PMID
1075:PMID
1024:PMID
975:PMID
923:PMID
866:PMID
818:PMID
764:PMID
713:PMID
685:Cell
662:PMID
622:PMID
582:ISBN
551:PMID
492:PMID
368:and
245:and
211:and
161:and
151:and
111:ESTs
103:cDNA
84:mRNA
56:gene
1305:doi
1301:274
1264:PMC
1256:doi
1252:164
1215:PMC
1207:doi
1166:PMC
1158:doi
1114:PMC
1106:doi
1065:PMC
1055:doi
1014:PMC
1006:doi
1002:347
965:PMC
957:doi
913:PMC
905:doi
856:hdl
848:doi
808:PMC
800:doi
754:PMC
744:doi
703:hdl
693:doi
689:165
654:doi
614:doi
574:doi
541:PMC
531:doi
484:doi
379:as
356:or
340:or
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