Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene. APAF-1 and CED-4 homologs have been found in all currently sequenced animal genomes.

Function

This gene encodes a cytoplasmic protein that forms one the central hubs in the apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 regulatory network. This protein contains (from the N terminal) a caspase recruitment domain (CARD

CARD domain

Caspase recruitment domains, or Caspase activation and recruitment domains , are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct...

), an ATPase

ATPase

ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...

 domain (NB-ARC), few short helical domains and then several copies of the WD40 repeat

WD40 repeat

The WD40 repeat is a short structural motif of approximately 40 amino acids , often terminating in a tryptophan-aspartic acid dipeptide...

 domain. Upon binding cytochrome c

Cytochrome c

The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...

 and dATP

Deoxyadenosine triphosphate

Deoxyadenosine triphosphate is a nucleoside triphosphate used in cells for DNA synthesis.-External links:KEGG entry on...

, this protein forms an oligomeric apoptosome

Apoptosome

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal or external cell death stimulus...

. The apoptosome binds and cleaves caspase 9 preproprotein, releasing its mature, activated form. The precise mechanism for this reaction is still debated though work published by Guy Salvesen

Guy Salvesen

Guy Salvesen is a South African-born biochemist, best known for his work in the field of apoptosis. His research focuses on proteases and their inhibitors in humans, with particular emphasis on the caspases of the apoptotic cell death pathway....

 suggests that the apoptosome may induce caspase 9 dimerization and subsequent autocatalysis

Autocatalysis

A single chemical reaction is said to have undergone autocatalysis, or be autocatalytic, if the reaction product itself is the catalyst for that reaction....

. Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.

Alternative splicing

Alternative splicing

Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...

 results in several transcript variants encoding different isoforms.

Structure

The first crystal structure

Crystal structure

In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...

 of the first two (CARD and NB-ARC) domains of the Apaf-1 protein was solved in the laboratory of Yigong Shi

Yigong Shi

-Career:Dr. Shi, who received PhD in Biophysics from Johns Hopkins University in 1995, has determined the crystal structure of several critical apoptotic proteins, including apaf-1, DIAP1, and the BIR3 domain of XIAP. He was the Warner-Lambert/Parke-Davis Professor in the department of Molecular...

. It contains a CARD domain

CARD domain

Caspase recruitment domains, or Caspase activation and recruitment domains , are interaction motifs found in a wide array of proteins, typically those involved in processes relating to inflammation and apoptosis. These domains mediate the formation of larger protein complexes via direct...

 with a Greek key motif composed of six helices, a Rossman fold nucleotide binding domains, a short helical motif and a winged-helix domain.

Interactions

APAF1 has been shown to interact

Protein-protein interaction

Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...

 with NLRP1

NLRP1

NACHT, LRR and PYD domains-containing protein 1 is a protein that in humans is encoded by the NLRP1 gene.-Interactions:NLRP1 has been shown to interact with caspase 9 and APAF1.-Further reading:...

, Caspase-9

Caspase-9

Caspase-9 is an initiator caspase, encoded by the CASP9 gene.CASP9 orthologs have been identified in all mammals for which complete genome data are available. Unique orthologs are also present in lizards, lissamphibians, and teleosts....

, APIP

APIP

APAF1-interacting protein is a protein that in humans is encoded by the APIP gene.-Further reading:...

, BCL2-like 1

BCL2-like 1 (gene)

Bcl-2-like protein 1 is a protein that in humans is encoded by the BCL2L1 gene.-Interactions:BCL2-like 1 has been shown to interact with RAD9A, RTN1, BAK1, Reticulon 4, Bcl-2-associated X protein, BCAP31, Bcl-2-interacting killer, PPP1CA, Noxa, VDAC1, BCL2L11, Bcl-2-associated death promoter,...

 and HSPA4

HSPA4

Heat shock 70 kDa protein 4 is a protein that in humans is encoded by the HSPA4 gene.The protein encoded by this gene was originally suggested to be a member of the heat shock protein 70 family...

.

Further reading