This family consists of several mammalian specific BCL2/adenovirus E1B 19kDa protein-interacting protein 3 or BNIP3 sequences. BNIP3 belongs to the Bcl-2 homology 3 (BH3)-only family, a Bcl-2-related family possessing an atypical Bcl-2 homology 3 (BH3) domain, which regulates PCD from mitochondrial sites by selective Bcl-2/Bcl-XL interactions. BNIP3 family members contain a C-terminal transmembrane domain that is required for their mitochondrial localisation, homodimerisation, as well as regulation of their pro-apoptotic activities. BNIP3-mediated apoptosis has been reported to be independent of caspase activation and cytochrome c release and is characterised by early plasma membrane and mitochondrial damage, prior to the appearance of chromatin condensation or DNA fragmentation [].
Cadherins (CADHs) are transmembrane glycoproteins vital in calcium-dependent cell-cell adhesion during tissue differentiation []. CADHs also have a crucial role in epithelial-to-mesenchymal transition (EMT), involved in migration properties of tumor cells. CADH6 is an EMT marker in thyroid cancer that interacts with the ATG8 family members GABARAP, BNIP3 and BNIP3L restraining autophagy through LIR (LC3 Interacting Regions, also known as ATG8-interacting motifs, AIMs) domains, a common feature among many cadherin family members [, ]. LIRs are short-linear motifs (SLiMs) of autophagy receptors and adaptor proteins that facilitates the selective recruitment of autophagy substrates to the autophagosome. They are characterised by degenerated sequences with a four-residue core central sequence involved in ATG8-binding, with the W/Y/FxxL/I/V pattern. Based on the aromatic amino acid in position 1 they can be classified into W-type, Y-type and F-type []. This entry includes three conserved LIR motifs of CADHs, which two are Y-type (YDxL/I) and one F-type (FKKL), while a fourth LIR (YGGV) is only present in CADH6 members [].
