173:
31:
319:(TFs) find their binding sites by facilitated diffusion, a combination of free diffusion in 3D and 1D-sliding on the DNA. During sliding the repressor is in contact with the DNA helix, sliding around and tracking its major groove, which speeds up the search process by extending the target length when the TF slides in onto the operator from the side.
37:. Two monomers (of four total) co-operate to bind each DNA operator sequence. Monomers (red and blue) contain DNA binding and core domains (labeled) which are connected by a linker (labeled). The C-terminal tetramerization helix is not shown. The repressor is shown in complex with operator DNA (gold) and ONPF (green), an anti-inducer ligand (
346:
almost always make a very short journey before finding the way back again. On the macroscopic scale, this looks like a stable interaction. This binding mechanism explains how DNA binding proteins manage to quickly search through the genome of the cell without getting stuck too long at sequences that resemble the true target.
287:
345:
experiments have shown that it is this probability to recognize the operator that changes with DNA sequence, while the time the TF remains in the bound conformation on the operator changes less with sequence. The TF often leaves the sequence it is intended to regulate, but at a strong target site, it
1138:
Marklund, Emil; van Oosten, Brad; Mao, Guanzhong; Amselem, Elias; Kipper, Kalle; Sabantsev, Anton; Emmerich, Andrew; Globisch, Daniel; Zheng, Xuan; Lehmann, Laura C.; Berg, Otto G.; Johansson, Magnus; Elf, Johan; Deindl, Sebastian (2020). "DNA surface exploration and operator bypassing during target
155:
repressor is unable to bind tightly to its cognate operator. Thus, the gene is mostly off in the absence of inducer and mostly on in the presence of inducer, although the degree of gene expression depends on the number of repressors in the cell and on the repressor's DNA-binding affinity.
331:
cells have now tested and verified the facilitated diffusion model, and shown that the TF scans on average 45 bp during each sliding event, before the TF detaches spontaneously and resumes exploring the genome in 3D. These experiments also suggest that LacI slides over the
336:
operator several times before binding, meaning that different DNA sequences can have different probabilities to be recognized at each encounter with the TF. This implies a trade-off between fast search on nonspecific sequences and binding to specific sequences.
76:
is not available to the cell, ensuring that the bacterium only invests energy in the production of machinery necessary for uptake and utilization of lactose when lactose is present. When lactose becomes available, it is firstly converted into
291:
294:
293:
289:
288:
295:
292:
385:
cells less accessible for the repressor. The existence of hopping, where the protein slips out of the major groove of DNA to land in another nearby groove along the DNA chain, has been proven more directly
183:
functional subunits (red+blue and green+orange) each bind a DNA operator sequence (labeled). These two functional subunits are coupled at the tetramerization region (labeled); thus, tetrameric
900:
Hammar, Petter; Leroy, Prune; Mahmutovic, Anel; Marklund, Erik G.; Berg, Otto G.; Elf, Johan (2012-06-22). "The lac
Repressor Displays Facilitated Diffusion in Living Cells".
1276:
135:, with base contacts also made by residues of symmetry-related alpha helices, the "hinge" helices, which bind deeply in the minor groove. This bound repressor can reduce
854:
Berg, Otto G.; Winter, Robert B.; Von Hippel, Peter H. (1981-11-01). "Diffusion-driven mechanisms of protein translocation on nucleic acids. 1. Models and theory".
203:. More precisely, the tetramer contains two DNA-binding subunits composed of two monomers each (a dimer of dimers). Each monomer consists of four distinct regions:
290:
464:
Schumacher MA, Choi KY, Zalkin H, Brennan RG (November 1994). "Crystal structure of LacI member, PurR, bound to DNA: minor groove binding by alpha helices".
275:. Additionally, because each tetramer contains two DNA-binding subunits, binding of multiple operator sequences by a single tetramer induces DNA looping.
394:
repressor has been observed to bypass operators, flip orientation, and rotate with a longer pitch than the 10.5 bp period of DNA while moving along it.
157:
1314:
1460:
172:
1014:
Marklund, Erik G.; Mahmutovic, Anel; Berg, Otto G.; Hammar, Petter; Spoel, David van der; Fange, David; Elf, Johan (2013-12-03).
959:
Marklund, Emil; Mao, Guanzhong; Yuan, Jinwen; Zikrin, Spartak; Abdurakhmanov, Eldar; Deindl, Sebastian; Elf, Johan (2022-01-28).
1664:
1273:
1083:"What matters for lac repressor search in vivo—sliding, hopping, intersegment transfer, crowding on DNA or recognition?"
1762:
1307:
379:
repressor includes intersegment transfer and hopping as well as crowding by other proteins which make the genome in
1340:
311:
the search is 10-100 times faster than the theoretical upper limit for two particles searching for each other via
160:(IPTG) is a commonly used allolactose mimic which can be used to induce transcription of genes being regulated by
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Each monomer has 360 amino acids, so it has 1440 amino acids in total, and 154,520 Dalton of atomic mass.
1731:
1726:
1594:
1496:
94:
24:
371:
for dissociation, implying that the repressor will slide over 8 bp on average before dissociating. The
773:
1628:
1542:
1508:
1402:
1214:
1148:
1027:
909:
811:
Riggs, Arthur D.; Bourgeois, Suzanne; Cohn, Melvin (1970). "The lac represser-operator interaction".
520:
473:
415:
407:
316:
1611:
1579:
1465:
1439:
272:
566:"Tuning Transcriptional Regulation through Signaling: A Predictive Theory of Allosteric Induction"
30:
1380:
1180:
996:
941:
433:
350:
200:
117:
97:, thereby genes coding for proteins involved in lactose uptake and utilization can be expressed.
82:
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489:
315:
in three dimensions (3D). To explain the fast search, it was hypothesized that LacI and other
1016:"Transcription-factor binding and sliding on DNA studied using micro- and macroscopic models"
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1222:
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143:
binding site or by prompting DNA looping. When lactose is present, allolactose binds to the
113:
110:
1485:
1280:
509:"Comparison of the theoretical and real-world evolutionary potential of a genetic circuit"
53:
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operator sequence slightly overlaps with the promoter, which increases the affinity of
140:
1237:
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749:
724:
1751:
1184:
1000:
824:
300:
Animation of binding and unbinding mechanism of a LacI dimer and its target DNA site.
945:
564:
Razo-Mejia M, Barnes S, Belliveau N, Chure G, Einav T, Lewis M, Phillips R (2018).
121:
622:
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1584:
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that connects the DNA-binding domain with the core domain (sometimes called the
78:
1207:
Proceedings of the
National Academy of Sciences of the United States of America
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for the promoter sequence such that it cannot enter elongation and remains in
148:
129:
86:
65:
1168:
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971:(6579). American Association for the Advancement of Science (AAAS): 442–445.
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simulation suggests that the transcription factor encounters a barrier of 1
312:
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Razo-Mejia M, Boedicker J, Jones D, DeLuna A, Kinney J, Phillips R (2014).
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61:
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961:"Sequence specificity in DNA binding is mainly governed by association"
321:
73:
69:
1355:
177:
Tetrameric LacI binds two operator sequences and induces DNA looping.
125:
251:
and is targeted to one of several operator DNA sequences (known as O
1616:
1468:
285:
171:
29:
20:
1687:
1517:
1448:
429:
57:
1296:
725:"The three operators of the lac operon cooperate in repression"
723:
Oehler S, Eismann ER, Krämer H, Müller-Hill B (April 1990).
222:, which binds allolactose, an allosteric effector molecule)
1081:
Mahmutovic, Anel; Berg, Otto G.; Elf, Johan (2015-03-16).
676:"Allostery in the LacI/GalR family: variations on a theme"
211:(in which two LacI proteins bind a single operator site)
305:
LacI finds its target operator DNA surprisingly fast.
187:
binds two operator sequences. This allows tetrameric
93:
repressor bound with allolactose is inhibited due to
240:(which joins four monomers in an alpha-helix bundle)
1708:
1673:
1647:
1572:
1530:
1507:
1484:
1420:
1413:
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862:(24). American Chemical Society (ACS): 6929–6948.
233:, which is important for allosteric communication)
52:(LacI) is a DNA-binding protein that inhibits the
1020:Proceedings of the National Academy of Sciences
151:change in its shape. In its changed state, the
19:"lacI" redirects here. Not to be confused with
669:
667:
1308:
72:in bacteria. These genes are repressed when
8:
35:Annotated crystal structure of dimeric LacI
1417:
1345:
1315:
1301:
1293:
636:Lewis M (June 2005). "The lac repressor".
89:) in bacteria. The DNA binding ability of
1265:at the U.S. National Library of Medicine
1236:
1226:
1114:
1057:
1039:
748:
699:
674:Swint-Kruse L, Matthews KS (April 2009).
589:
540:
424:the protein bound to DNA containing the
456:
1461:Histone acetylation and deacetylation
895:
893:
613:Goodsell DS (2003). "Lac Repressor".
428:operon, and it released the DNA when
282:Kinetics of DNA binding and unbinding
244:DNA binding occurs via an N-terminal
158:Isopropyl β-D-1-thiogalactopyranoside
139:of the Lac proteins by occluding the
7:
120:, binding base-specifically to the
741:10.1002/j.1460-2075.1990.tb08199.x
14:
1201:, Müller-Hill B (December 1966).
325:single-molecule experiments with
1203:"Isolation of the lac repressor"
1665:Archaeal transcription factor B
680:Current Opinion in Microbiology
109:repressor (LacI) operates by a
772:Lewis, Mitchell (2005-06-01).
1:
533:10.1088/1478-3975/11/2/026005
1287:Lac Repressor in Proteopedia
825:10.1016/0022-2836(70)90074-4
813:Journal of Molecular Biology
436:of allolactose) was added.
41:a stabilizer of DNA binding)
819:(3). Elsevier BV: 401–417.
780:. Retour sur l'operon lac.
623:10.2210/rcsb_pdb/mom_2003_3
1779:
1341:Transcriptional regulation
1274:the lac repressor molecule
790:10.1016/j.crvi.2005.04.004
650:10.1016/j.crvi.2005.04.004
582:10.1016/j.cels.2018.02.004
418:in 1966. They showed that
18:
1538:Transcription coregulator
1474:Histone acetyltransferase
1444:Histone methyltransferase
1422:Histone-modifying enzymes
1161:10.1038/s41586-020-2413-7
692:10.1016/j.mib.2009.01.009
1267:Medical Subject Headings
778:Comptes Rendus Biologies
638:Comptes Rendus Biologies
1639:Internal control region
1041:10.1073/pnas.1307905110
977:10.1126/science.abg7427
922:10.1126/science.1221648
486:10.1126/science.7973627
199:repressor protein is a
1228:10.1073/pnas.56.6.1891
1087:Nucleic Acids Research
615:RCSB Protein Data Bank
363:during sliding and 12
302:
238:tetramerization region
218:(sometimes called the
192:
191:to induce DNA looping.
147:repressor, causing an
42:
1732:Intrinsic termination
1497:DNA methyltransferase
375:search model for the
317:transcription factors
298:
175:
95:allosteric regulation
33:
1509:Chromatin remodeling
1272:More information on
406:repressor was first
1466:Histone deacetylase
1456:Histone demethylase
1440:Histone methylation
1283:on protein database
1219:1966PNAS...56.1891G
1153:2020Natur.583..858M
1032:2013PNAS..11019796M
1026:(49): 19796–19801.
914:2012Sci...336.1595H
908:(6088): 1595–1598.
868:10.1021/bi00527a028
774:"The lac repressor"
525:2014PhBio..11b6005R
478:1994Sci...266..763S
273:abortive initiation
16:DNA-binding protein
1763:Bacterial proteins
1279:2010-05-28 at the
1099:10.1093/nar/gkv207
351:molecular dynamics
303:
209:DNA-binding domain
195:Structurally, the
193:
118:DNA-binding domain
43:
1745:
1744:
1700:RNA polymerase II
1568:
1567:
1526:
1525:
1147:(7818): 858–861.
416:Benno Müller-Hill
296:
216:regulatory domain
1770:
1622:Response element
1605:Response element
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513:Physical Biology
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472:(5186): 763–70.
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249:structural motif
246:helix-turn-helix
111:helix-turn-helix
64:involved in the
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137:transcription
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856:Biochemistry
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735:(4): 973–9.
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570:Cell Systems
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390:, where the
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349:An all-atom
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201:homotetramer
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179:Two dimeric
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130:
122:major groove
106:
104:
90:
47:
46:
44:
38:
34:
1709:Termination
1585:Pribnow box
1553:Corepressor
1548:Coactivator
1349:prokaryotic
231:hinge helix
220:core domain
164:repressor.
79:allolactose
60:coding for
1752:Categories
1737:Rho factor
1727:Terminator
1718:eukaryotic
1693:eukaryotic
1674:Elongation
1660:Eukaryotic
1648:Initiation
1431:nucleosome
1414:eukaryotic
1386:gal operon
1381:ara operon
1376:Gua Operon
1371:gab operon
1366:trp operon
1361:lac operon
1332:Eukaryotic
452:References
446:Lac operon
149:allosteric
66:metabolism
54:expression
1713:bacterial
1681:bacterial
1655:Bacterial
1629:Insulator
1573:Promotion
1543:Activator
1393:Repressor
1328:Bacterial
1199:Gilbert W
1185:220049852
1169:0028-0836
1139:search".
1107:1362-4962
1050:0027-8424
1001:246360459
985:0036-8075
930:0036-8075
876:0006-2960
833:0022-2836
798:1631-0691
398:Discovery
313:diffusion
263:). The O
168:Structure
50:repressor
1634:Silencer
1612:Enhancer
1600:CAAT box
1590:TATA box
1580:Promoter
1277:Archived
1247:16591435
1177:32581356
1125:25779051
1068:24222688
993:35084952
946:21351861
938:22723426
710:19269243
658:15950160
600:29574055
551:24685590
440:See also
421:in vitro
408:isolated
388:in vitro
343:in vitro
308:In vitro
101:Function
62:proteins
1560:Inducer
1427:histone
1215:Bibcode
1149:Bibcode
1116:4402528
1059:3856812
1028:Bibcode
965:Science
910:Bibcode
902:Science
884:7317363
841:4924006
759:2182324
701:2688824
591:5991102
542:4051709
521:Bibcode
494:7973627
474:Bibcode
466:Science
382:E. coli
373:in vivo
339:In vivo
328:E. coli
322:In vivo
128:of the
124:of the
116:in its
74:lactose
70:lactose
1356:Operon
1269:(MeSH)
1245:
1238:220206
1235:
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1141:Nature
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434:analog
227:linker
133:operon
1617:E-box
1469:HDAC1
1181:S2CID
997:S2CID
942:S2CID
259:and O
114:motif
58:genes
21:lac I
1688:rpoB
1531:both
1518:CHD7
1449:EZH2
1243:PMID
1173:PMID
1165:ISSN
1121:PMID
1103:ISSN
1064:PMID
1046:ISSN
989:PMID
981:ISSN
934:PMID
926:ISSN
880:PMID
872:ISSN
837:PMID
829:ISSN
794:ISSN
755:PMID
706:PMID
654:PMID
596:PMID
547:PMID
490:PMID
432:(an
430:IPTG
414:and
402:The
341:and
189:LacI
185:LacI
181:LacI
105:The
87:lacZ
45:The
39:i.e.
25:Laci
1595:BRE
1233:PMC
1223:doi
1157:doi
1145:583
1111:PMC
1095:doi
1054:PMC
1036:doi
1024:110
973:doi
969:375
918:doi
906:336
864:doi
821:doi
786:doi
782:328
745:PMC
737:doi
696:PMC
688:doi
646:doi
642:328
619:doi
586:PMC
578:doi
537:PMC
529:doi
482:doi
470:266
426:lac
410:by
404:lac
392:lac
377:lac
255:, O
197:lac
162:lac
153:lac
145:lac
131:lac
107:lac
91:lac
81:by
68:of
56:of
48:lac
23:or
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367:B
365:k
360:T
358:B
356:k
334:1
332:O
265:1
261:3
257:2
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