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Nejasni kompleks

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NMR-na struktura inhibitora ciklin-zavisne kinaze Sic1 sa ubikvitin-ligazom Cdc4 (siva). Od devet fosforilacijskih mjesta Sic 1 (sfere) prikazani su kontakti sa T45 i S76 (narandžasti i plavi).
Nejasna veza (prikazana isprekidanom linijom) ultrabitoraksnog faktora transkripcija (narandžasta) povezuje homedomene i ekstradentikulni homedomen (plava) (PDB kôd 1bi). Alternativno spajanje modulira dužinu nejasnog područja, a time i afinitet vezanja njegove DNK (siva) Ostala regulatorna nejasna područja ultrabitoraksa također su prikazana tačkastim linijama

Nejasni kompleksi ili neizraziti kompleksi su proteinski kompleksi, gdje postoji strukturna dvosmislenost ili postojeća višestrukost i potrebni su za biološke funkcije.[1][2] Promjena, skraćivanje ili uklanjanje konformacijski dvosmislenih regija utiče na aktivnost odgovarajućih kompleksa.[3][4][5] Nejasne komplekse uglavnom formiraju [[suštinski nestrukturirani proteini| suštinski poremećeni proteini.[6][7] Strukturna multiplikacija obično leži u osnovi funkcijske višestrukosti proteinskih kompleksa[8][9][10] slijedeći nejasnu logiku. Izraziti načini vezanja nukleosoma također se smatraju posebnim nejasnim slučajem.[11][12]

Historijska pozadina

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Gotovo 50 godina molekulska biologija temeljila se na dvije dogme: (1) izjednačavanju biološke funkcije proteina s jedinstvenom trodimenzijskom strukturom i (2) pretpostavljanju izuzetne specifičnosti u proteinskim kompleksima. Specifičnost/ elektivnost osigurava se nedvosmislenim skupom interakcija formiranih između proteina i njegovog liganda (drugog proteina, DNK, RNK ili male molekule). Mnogi proteinski kompleksi, međutim, sadrže funkcijski važne / kritične regije, koje ostaju vrlo dinamične u kompleksu ili usvajaju različite konformacije .[13] Ovaj fenomen definira se nejasnošću. Najvažniji primjer je ciklin-zavisni inhibitor kinaze Sic1, koji se veže za SCF podjedinicu Cdc4 u fosforilacijski ovisnom postupku.[14] Neregularne sekundarne strukture se postižu nakon fosforilacije, uz izmjenu različitih mjesta fosforilacije u kompleksu.[15]

Klasifikacija nejasnih kompleksa

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Strukturna dvosmislenost u proteinskim kompleksima pokriva širok spektar.[1] U polimorfnom kompleksu, protein usvaja dvije ili više različitih konformacija, nakon vezanja za istog partnera i te se konformacije mogu riješiti.[16] Clamp,[17] flankiranjem (bočnom konfiguracijom) [18][19] i slučajnim kompleksima,[20][21] koji su dinamični, gdje se dvosmislene konformacije međusobno izmjenjuju i ne mogu se riješiti. Interakcije u nejasnim kompleksima obično posreduju kratki motivi.[22] Bočni regioni tolerantni su na promjene sekvence sve dok se održava aminokiselinska kompozicija, naprimjer u slučaju histonskih linker C-krajnjih domena [23] i H4 histona domena N-kraja.[24]

Regulacijski putevi preko nejasne regija

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Nejasna područja moduliraju konformacijsku ravnotežu [25] ilu fleksibilnost [3][26] interfejsa vezanja, putem privremene interakcije.[27] Dynamic regions can also compete with binding sites[28] or tether them to the target.[29] Modifikacije nejasnih područja daljnjim interakcijama,[8][30] ili posttranslacijskim modifikacijama[31][32] utiču na afinitet vezanja ili specifičnost. Alternativna prerada mogu modulirati dužinu nejasnih regija, što rezultira vezanjem ovisno o kontekstu (npr. tkivno-specifičnos) na kompleksu.[33][34][35] EGF / MAPK, TGF-β i WNT/beskrilni signalni putevi koriste nejasna područja specifična za tkivo.

Reference

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