AP-5 complex subunit mu (AP5M1), otherwise known as MUDENG (MuD), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that is encoded by the ''AP5M1''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. The AP5M1 gene was originally discovered when screening for genes which helped to promote death in Fas-mediated apoptosis. It is a highly conserved gene. MuD is the medium-sized subunit of the AP5 adaptor complex. MuD is expressed throughout the body and is located within both the mitochondria as well as the endoplasmic reticulum (ER) of cells. MuD has been shown to have the ability to induce apoptosis; however, there is evidence that it plays an anti-apoptotic role in apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Structure

MuD consists of 490 amino acids that interact to form a

tertiary structure Protein tertiary structure is the three dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains may int ...

with three domains. The overall structure shares similarities with adaptor protein (AP) complexes that are related to

clathrin-mediated endocytosis Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This ...

; amino acids 197 through 417 are a shared adaptin domain found in AP μ subunits. Within the adaptin domain are two aspartic acids, D276 and D290, which serve as

binding sites In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

for

caspase-3 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also ...

Function

The overall function of MuD remains unclear. It is known, however, that MuD regulates the

expression Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, ...

of BAX, a pro-apoptotic member of the Bcl-2 family of proteins. Due to— and dependent upon— this relationship, MuD has been able to induce cell death in tumor cells. Additionally, MuD has been suggested to be involved in endosomal trafficking.

TRAIL and MuD

TRAIL, an apoptosis-inducing

ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...

, activates

caspase-8 Caspase-8 is a caspase protein, encoded by the ''CASP8'' gene. It most likely acts upon caspase-3. ''CASP8'' orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present ...

and caspase-3, which initiate the intrinsic pathway of apoptosis by cleaving BH3 interacting-domain death agonist (Bid) into tBid, another pro-apoptotic member of the Bl-2 protein family. MuD interferes with this process because D276 and D290 act as alternative binding sites for caspase-3, decreasing the amount of Bid that gets cleaved. Tumor cells being treated with TRAIL are 32% more likely to survive when MuD is being expressed.

References

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