Family of proteins BCL-2

Kako bi se održala homeostaza broja stanica u nekom organizmu, milijarde stanica dnevno umiru uslijed procesa apoptoze. Egzekutorsko djelovanje u ovom procesu vrše cisteinske proteaze kaspaze potaknute različitim stresnim signalima. No, u procesu apoptoze bitnu ulogu imaju i proteini iz porodice BCL-2. Ti su proteini isprva deklarirani isključivo kao antiapoptički proteini koji uvelike doprinose nastanku i održavanju tumora. U zadnjih petnaestak godina te su tvrdnje dijelom opovrgnute zbog izolacije strukturno veoma sličnih proteina, čija je aktivacija dovodila do procesa apoptoze. Sličnosti između antiapoptičkih i proapoptičkih proteina BCL-2 očitovale su se u visoko konzerviranim BH domenama, obliku aktivnog mjesta enzima – dubokom hidrofobnom žljebu BC zatvorenom s nekoliko amfipatskih zavojnica, te načinu aktivacije/inhibicije. Osim toga, aktivno mjesto geometrijski i termodinamički odgovara obliku BH3 regije ove skupine proteina. Kako bi inducirali apoptozu, proapoptički proteini se vežu na vanjsku membranu mitohondrija i oligomeriziraju se stvarajući proteinske kanale za izlazak citokroma c iz matriksa mitohondrija – signala za aktivaciju kaspaza. Antiapoptički proteini BCL-2 mogu se vezati na proapoptičke članove i tako ih direktno inaktivirati kako bi očuvali integritet membrane. No, mitohondrijska membrana nije jedino područje gdje ovi proteini djeluju, tj. provedena su mnoga istraživanja koja upućuju na veliku važnost ovih proteina u održavanju koncentracije kalcija u endoplazmatskom retikulumu i citosolu, kao i u procesu autofagije – evolucijske alternative procesu apoptoze. Proteini BCL-2 su regulirani na transkripcijskoj, posttranskripcijskoj i posttranslacijskoj razini. Također za regulaciju su važne interakcije s ostalim članovima porodice BCL-2 – antiapoptički i efektorski proteini se međusobno inhibiraju, dok proteini koji sadrže samo BH3 domenu mogu djelovati kao aktivatori efektorskih proteina i/ili inhibitori proapoptičkih proteina. To maintain homeostasis in a number of cells in the body of vertebrates, billions of cells die every day in the process called apoptosis. Apoptosis is executed through the action of cystein proteases caspases induced by different stress signals. However, in the process of apoptosis an important role has a family of proteins called BCL-2. These proteins were initially declared only as antiapoptotic proteins that greatly contribute to the tumorogenesis. In the last fifteen years, on the other side, structurally were isolated very similar proteins whose activation led to apoptosis. Similarities between antiapoptotic and proapoptotic BCL-2 proteins are reflected in the highly conserved BH domains, in the shape of the enzyme active site - a deep hydrophobic BC groove closed with several amphipathic helixes, and in the way of activation / inhibition. In addition, active site geometrically and thermodynamically matches a BH3 region of this group of proteins. In order to induce apoptosis, proapoptotic proteins bind to the outer mitochondrial membrane and oligomerize to form protein channels for cytochrome c release from the mitochondrial matrix – the signal for caspase activation. Antiapoptotic BCL-2 proteins interact with proapoptotic members and directly inactivate them in order to protect membrane integrity. The mitochondrial membrane is not the only place of their action. There were done many experiments suggesting the role of these proteins in the maintenance Ca2+ concentration in the ER and cytosol and in the process called autophagy – evolutionary alternative for the apoptosis process. BCL-2 proteins are regulated at transcriptional, posttranscriptional and posttranslational level. Interactions with other members of the BCL-2 family are also important for regulation: antiapoptotic and effector proteins inhibit each other, and proteins containing only BH3 domain act as activators of effector proteins and / or inhibitors of proapoptotic proteins.