Autophagy is the main pathway of catabolism for breakdown and recycling of organelles and proteins.Zhenyu Yue.2009Itis a major pathway of degradation in a cell. The cytosolic material is sequestered into membrane vesicles called autophagosomes, and then delivered to the lysosome for degradation. In eukaryotic cells this process of autophagy is highly conserved. Ralph A,2012 Fig 1.Moreover this process is very important in maintaining cellular homoeostasis, whereas defects in this process may contribute to certain diseases likeneurodegenerative disorders, infectious diseases, and metabolic disorders. Jihoon Nah, 2015.Apart from these role autophagy play a very important role in immunity i.e., both innate and adaptive immunity via acting as regulator of inflammatory response, pathogen clearances and antigen presentation. the complex network of proteins is involved in regulation of autophagy that include mammalian target of rapamycin, the class III phosphatidylinositol-3 kinase/Beclin 1 complex, and two ubiquitin-like conjugation systems.Beclin 1 was described first in mammalian autophagy protein and as a central part of the class III phosphatidylinositol 3-kinase (PI3K-III) complex, Kihara A, 2001. Beclin 1 is involved in other functions like in membrane trafficking and restructuring involved in autophagy, endocytosis, cytokinesis and phagocytosis.Beclin has central role in autophagy. Beclin induces autophagy via interaction with several cofactors like UVRAG,Atg14L, Bif-1, Rubicon, Ambra1, HMGB1, VMP1, nPIST, SLAM, IP3R, PINK and survivin. Furthermore, Beclin 1 consists of BH3 domain which is bound to and inhibited by Bcl-2 or Bcl-XL.Zalckvar E,2009.This interaction can be disrupted by phosphorylation of Bcl-2 and Beclin 1, or ubiquitination of Beclin 1. Interestingly, caspase-mediated cleavage of Beclin 1 promotes crosstalk between apoptosis and autophagy.Saeid Ghavami,2014
Beclin 1 was discovered earlier as a B-cell lymphoma-2 (Bcl-2) interacting partner. Beclin 1 is present on human chromosome number 17q21. Zidong Li, Bo Chen,2010.Various studies demonstrated that Beclin1 couldinhibit tumorigenesis and restore autophagic activity in Atg6-disrupted yeast, designating Beclin1 as an autophagy regulator and tumor suppressor gene.Yue z ,etal,2003. 30 % sequence identity of beclin 1 is similar to its yeast orthologATG6/VPS30.Zhenyu Yue,2003In mammals beclin 1 appears to be an obligate component comprising of two different complexes one involving human ortholog ATG14/Barkor and other involving UVRAG.Weijiao Huang,2012
Beclin is 450 amino acid protein which contains three domains: a short BH3 motif of residues 105-125, a coiled-coil segment, and a C-terminal half comprising of conserved domain ECD of residues 244-337. The ECD domain forms a compact ellipsoid with four ?-helices (?1-?4), three pairs of anti-parallel ?-strands (?1-?6) and six intervening loops.
Three internal repeats are formed from these elements. The surface of ECD is very charged. It is important to mediate autophagy and to inhibit tumorigenesis. The interaction of Bcl-2 family proteins occurs via BH3 domain. Furthermore, the coiled coil segment is involved in dimerizationwith other proteins such as UVRAG and ATG14/Barkor. Apart from these structural elements Beclin 1 also contains a short leucine-rich amino acid sequence that is responsible for its efficient nuclear export signal (NES).Mutations of NES interfere with its abilities to promote nutrient deprivation-induced autophagy and suppress tumorigenesis.