184:. The LNS2 domain targets the C-terminus of Nir1 to the plasma membrane in order to allow the protein to bridge the ER-PM MCS. Deletion of this domain results in Nir1 localization to the ER. It should be noted however, that the exact domain boundaries of the LNS2 domain are still being debated, especially given the boundaries of the folded domains predicted by the AlphaFold Protein Structure Database. (
91:
201:
197:
ER-PM MCS, where they exchange the PA at the PM for PI that has been produced in the ER. As Nir1 is localized to the ER-PM MCS even without a stimulus, it is thought that Nir1 helps to recruit Nir2 to the MCS. There is evidence that Nir1 recruits Nir2 directly via binding to the uncharacterized domain between the FFAT and DDHD of Nir1
196:
The PITPNM family of proteins has been shown to participate in the phosphoinositide cycle. Lipids cycle between the PM and the ER in order to replenish levels after signaling events deplete lipid species such as PI.. When a stimulus results in the production of PA at the PM, Nir2 and Nir3 move to the
86:
homolog RdgBaII).. Nir1 shares high sequence similarity with Nir2 and Nir3, which led to its original categorization as a PITP. However, it was determined that Nir1 is not directly responsible for PI transfer, as it lacks the functional PITP domain seen within Nir2 and Nir3
167:
enzymes, which hydrolyze fatty acids of glycerolphospholipids, including phosphatidic acid (PA). However, this domain is still largely uncharacterized. It is a putative metal binding domain, but a role for metal binding in PITPNM function has not been established
180:/Smp2 domain. This domain was discovered as having sequence similarities to the phosphatidic acid (PA) binding region found within the Lipin family of proteins. It is also responsible for PA-binding within Nir1, as it has been shown to co-localize with PA
204:
Nir1 localizes to ER-PM MCS using its FFAT and LNS2 domains. It is thought to directly interact with Nir2 in order to recruit Nir2 to the ER-PM MCS, so that Nir2 can transfer lipids with its PITP domain.
782:
Jumper, John; Evans, Richard; Pritzel, Alexander; Green, Tim; Figurnov, Michael; Ronneberger, Olaf; Tunyasuvunakool, Kathryn; Bates, Russ; Ĺ˝Ădek, Augustin; Potapenko, Anna; Bridgland, Alex (2021-07-15).
155:. Mutation of the phenylalanine residues in this motif or knockout of the VAPA and VAPB proteins results in a loss of ER-PM MCS localization and causes Nir1 to become fully localized to the PM.
725:
Varadi, Mihaly; Anyango, Stephen; Deshpande, Mandar; Nair, Sreenath; Natassia, Cindy; Yordanova, Galabina; Yuan, David; Stroe, Oana; Wood, Gemma; Laydon, Agata; Ĺ˝Ădek, Augustin (2021-11-17).
107:(PLC) activation. Notably, PLC activation has previously been shown to regulate the localization of Nir2 and Nir3 at ER-PM MCS well.. The MCS-targeting by Nir1 is achieved by the
123:
Nir1 contains three main structural elements that are shared with Nir2 and Nir3: an N-terminal FFAT motif, a DDHD domain, and a C-terminal Lipin/Ndel/Smp2 (LNS2) domain.
67:
448:"Phosphatidylinositol 4,5-Bisphosphate Homeostasis Regulated by Nir2 and Nir3 Proteins at Endoplasmic Reticulum-Plasma Membrane Junctions"
147:
ract. This motif, made of residues EFFDA in Nir1, has been shown to be necessary for the Nir proteins to associate with the ER proteins
727:"AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models"
258:"Topological organisation of the phosphatidylinositol 4,5-bisphosphate–phospholipase C resynthesis cycle: PITPs bridge the ER–PM gap"
668:
Kim, SoHui; Kedan, Amir; Marom, Merav; Gavert, Nancy; Keinan, Omer; Selitrennik, Michael; Laufman, Orly; Lev, Sima (2013-07-30).
859:
670:"The phosphatidylinositol-transfer protein Nir2 binds phosphatidic acid and positively regulates phosphoinositide signalling"
611:"Phosphorylation of human phospholipase A1 DDHD1 at newly identified phosphosites affects its subcellular localization"
223:
864:
609:
Matsumoto, Naoki; Nemoto-Sasaki, Yoko; Oka, Saori; Arai, Seisuke; Wada, Ikuo; Yamashita, Atsushi (July 2021).
43:
35:
115:
of Nir1 localizing to the PM. The domains responsible for binding these membranes are discussed below.
376:"Nir1 constitutively localizes at ER–PM junctions and promotes Nir2 recruitment for PIP 2 homeostasis"
796:
47:
591:
536:
421:
854:
830:
812:
764:
746:
707:
689:
650:
632:
583:
575:
528:
487:
469:
413:
395:
349:
331:
287:
279:
163:
The DDHD domain, made up of 3 Asp and 1 His residues, bears some similarities to that seen in
71:
103:
Recently, Nir1 has been shown to localize to ER-PM MCS, both under basal conditions and upon
54:, potentially by recruiting additional proteins to the ER-PM MCS. It is encoded by the gene
820:
804:
754:
738:
697:
681:
640:
622:
567:
518:
477:
459:
403:
387:
339:
323:
269:
164:
104:
800:
374:
Quintanilla, Carlo
Giovanni; Lee, Wan-Ru; Liou, Jen (2022-03-01). Olzmann, James (ed.).
825:
759:
702:
645:
610:
482:
447:
408:
375:
344:
556:"Phosphatidylinositol transfer proteins and cellular nanoreactors for lipid signaling"
94:
The names, Drosophila homologs, and domain architecture of the PITPNM family proteins.
848:
540:
425:
39:
595:
784:
311:
90:
808:
327:
200:
627:
132:
112:
108:
816:
750:
693:
636:
579:
532:
523:
506:
473:
399:
335:
283:
669:
464:
391:
181:
834:
768:
742:
711:
685:
654:
587:
491:
417:
353:
291:
185:
726:
555:
274:
257:
51:
571:
75:
31:
74:(PA) between membranes. Class IIA PITPs are the multi-domain proteins
312:"Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation"
554:
Ile, Kristina E; Schaaf, Gabriel; Bankaitis, Vytas A (2006-10-18).
507:"Mammalian PITPs at the Golgi and ER-Golgi Membrane Contact Sites"
199:
89:
177:
152:
148:
785:"Highly accurate protein structure prediction with AlphaFold"
24:
membrane-associated phosphatidylinositol transfer protein 3
66:
Nir1 has been classically categorized as a class IIA
70:(PITP) that transfers phosphatidylinositol (PI) and
256:Cockcroft, Shamshad; Raghu, Padinjat (2016-11-25).
505:Cockcroft, Shamshad; Lev, Sima (January 2020).
8:
824:
758:
701:
644:
626:
522:
481:
463:
407:
343:
273:
446:Chang, Chi-Lun; Liou, Jen (June 2015).
215:
135:is made up of double phenylalanines (
111:of Nir1 localizing to the ER and the
68:phosphatidylinositol transfer protein
7:
441:
439:
437:
435:
369:
367:
365:
363:
305:
303:
301:
251:
249:
232:GeneCards: The Human Gene Database
16:A mammalian lipid transfer protein
14:
615:Journal of Biological Chemistry
452:Journal of Biological Chemistry
82:homolog RdgBaI), PITPNM2/Nir3 (
46:(MCS) and aids the transfer of
228:Gene - PITPNM Family Member 3"
1:
380:Molecular Biology of the Cell
176:The LNS2 domain is the Lipin/
186:Alphafold structure of Nir1
881:
809:10.1038/s41586-021-03819-2
328:10.1152/physrev.00028.2012
310:Balla, Tamas (July 2013).
628:10.1016/j.jbc.2021.100851
524:10.1177/2515256420964170
560:Nature Chemical Biology
465:10.1074/jbc.m114.621375
392:10.1091/mbc.E21-07-0356
731:Nucleic Acids Research
686:10.1038/embor.2013.113
206:
95:
44:membrane contact sites
860:Endoplasmic reticulum
316:Physiological Reviews
203:
93:
36:endoplasmic reticulum
743:10.1093/nar/gkab1061
275:10.1042/bcj20160514c
48:phosphatidylinositol
801:2021Natur.596..583J
572:10.1038/nchembio835
517:: 251525642096417.
458:(23): 14289–14301.
262:Biochemical Journal
207:
96:
50:between these two
34:that localizes to
795:(7873): 583–589.
737:(D1): D439–D444.
268:(23): 4289–4310.
72:phosphatidic acid
30:) is a mammalian
872:
865:Membrane biology
839:
838:
828:
779:
773:
772:
762:
722:
716:
715:
705:
665:
659:
658:
648:
630:
606:
600:
599:
551:
545:
544:
526:
502:
496:
495:
485:
467:
443:
430:
429:
411:
371:
358:
357:
347:
322:(3): 1019–1137.
307:
296:
295:
277:
253:
244:
243:
241:
239:
234:. 4 October 2023
220:
880:
879:
875:
874:
873:
871:
870:
869:
845:
844:
843:
842:
781:
780:
776:
724:
723:
719:
680:(10): 891–899.
667:
666:
662:
608:
607:
603:
566:(11): 576–583.
553:
552:
548:
504:
503:
499:
445:
444:
433:
373:
372:
361:
309:
308:
299:
255:
254:
247:
237:
235:
222:
221:
217:
212:
194:
174:
161:
129:
121:
105:phospholipase C
101:
64:
40:plasma membrane
17:
12:
11:
5:
878:
876:
868:
867:
862:
857:
847:
846:
841:
840:
774:
717:
660:
601:
546:
497:
431:
359:
297:
245:
214:
213:
211:
208:
193:
190:
173:
170:
160:
157:
128:
125:
120:
117:
100:
97:
63:
62:Classification
60:
15:
13:
10:
9:
6:
4:
3:
2:
877:
866:
863:
861:
858:
856:
853:
852:
850:
836:
832:
827:
822:
818:
814:
810:
806:
802:
798:
794:
790:
786:
778:
775:
770:
766:
761:
756:
752:
748:
744:
740:
736:
732:
728:
721:
718:
713:
709:
704:
699:
695:
691:
687:
683:
679:
675:
671:
664:
661:
656:
652:
647:
642:
638:
634:
629:
624:
621:(1): 100851.
620:
616:
612:
605:
602:
597:
593:
589:
585:
581:
577:
573:
569:
565:
561:
557:
550:
547:
542:
538:
534:
530:
525:
520:
516:
512:
508:
501:
498:
493:
489:
484:
479:
475:
471:
466:
461:
457:
453:
449:
442:
440:
438:
436:
432:
427:
423:
419:
415:
410:
405:
401:
397:
393:
389:
385:
381:
377:
370:
368:
366:
364:
360:
355:
351:
346:
341:
337:
333:
329:
325:
321:
317:
313:
306:
304:
302:
298:
293:
289:
285:
281:
276:
271:
267:
263:
259:
252:
250:
246:
233:
229:
227:
219:
216:
209:
202:
198:
191:
189:
187:
183:
179:
171:
169:
166:
158:
156:
154:
150:
146:
142:
138:
134:
126:
124:
118:
116:
114:
110:
106:
98:
92:
88:
85:
81:
77:
73:
69:
61:
59:
57:
53:
49:
45:
41:
37:
33:
29:
25:
21:
792:
788:
777:
734:
730:
720:
677:
674:EMBO Reports
673:
663:
618:
614:
604:
563:
559:
549:
514:
510:
500:
455:
451:
383:
379:
319:
315:
265:
261:
236:. Retrieved
231:
225:
218:
195:
175:
162:
144:
140:
136:
130:
122:
102:
99:Localization
83:
79:
65:
55:
27:
23:
19:
18:
172:LNS2 domain
159:DDHD domain
849:Categories
386:(3): br2.
238:4 December
210:References
182:biosensors
133:FFAT motif
127:FFAT motif
113:C-terminus
109:N-terminus
84:Drosophila
80:Drosophila
817:0028-0836
751:0305-1048
694:1469-221X
637:0021-9258
580:1552-4450
541:226531182
533:2515-2564
474:0021-9258
426:245927652
400:1059-1524
336:0031-9333
284:0264-6021
119:Structure
52:membranes
38:(ER) and
855:Proteins
835:34265844
769:34791371
712:23897088
655:34089703
596:39526983
588:17051233
492:25887399
418:35020418
354:23899561
292:27888240
192:Function
139:) in an
826:8371605
797:Bibcode
760:8728224
703:3807235
646:8234217
511:Contact
483:4505499
409:9250379
345:3962547
226:PITPNM3
78:/Nir2 (
76:PITPNM1
56:PITPNM3
32:protein
28:PITPNM3
833:
823:
815:
789:Nature
767:
757:
749:
710:
700:
692:
653:
643:
635:
594:
586:
578:
539:
531:
490:
480:
472:
424:
416:
406:
398:
352:
342:
334:
290:
282:
143:cidic
592:S2CID
537:S2CID
422:S2CID
42:(PM)
831:PMID
813:ISSN
765:PMID
747:ISSN
708:PMID
690:ISSN
651:PMID
633:ISSN
584:PMID
576:ISSN
529:ISSN
488:PMID
470:ISSN
414:PMID
396:ISSN
350:PMID
332:ISSN
288:PMID
280:ISSN
240:2023
178:Nde1
165:PLA1
153:VAPB
151:and
149:VAPA
131:The
20:Nir1
821:PMC
805:doi
793:596
755:PMC
739:doi
698:PMC
682:doi
641:PMC
623:doi
619:297
568:doi
519:doi
478:PMC
460:doi
456:290
404:PMC
388:doi
340:PMC
324:doi
270:doi
266:473
22:or
851::
829:.
819:.
811:.
803:.
791:.
787:.
763:.
753:.
745:.
735:50
733:.
729:.
706:.
696:.
688:.
678:14
676:.
672:.
649:.
639:.
631:.
617:.
613:.
590:.
582:.
574:.
562:.
558:.
535:.
527:.
513:.
509:.
486:.
476:.
468:.
454:.
450:.
434:^
420:.
412:.
402:.
394:.
384:33
382:.
378:.
362:^
348:.
338:.
330:.
320:93
318:.
314:.
300:^
286:.
278:.
264:.
260:.
248:^
230:.
188:)
137:FF
58:.
837:.
807::
799::
771:.
741::
714:.
684::
657:.
625::
598:.
570::
564:2
543:.
521::
515:3
494:.
462::
428:.
390::
356:.
326::
294:.
272::
242:.
224:"
145:T
141:A
26:(
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
