Saposin protein domain

The saposin domains refers to two evolutionally-conserved protein domains found in saposin and related proteins (SAPLIP). Saposins are small lysosomal proteins that serve as activators of various lysosomal lipid-degrading enzymes. They probably act by isolating the lipid substrate from the membrane surroundings, thus making it more accessible to the soluble degradative enzymes. All mammalian saposins are synthesized as a single precursor molecule (prosaposin) which contains four Saposin-B domains, yielding the active saposins after proteolytic cleavage, and two Saposin-A domains that are removed in the activation reaction.[2]

Saposin A-type domain
Identifiers
SymbolSapA
PfamPF02199
InterProIPR003119
PROSITEPDOC51110
Saposin-like type B, region 1 (SapB1)
Crystal structure of human saposin C dimer in an open conformation.[1]
Identifiers
SymbolSapB_1
PfamPF05184
InterProIPR007856
PROSITEPDOC50015
Saposin-like type B, region 2 (SapB2)
Identifiers
SymbolSapB_2
PfamPF03489
InterProIPR008138
PROSITEPDOC50015
CATH1qdmC03
SCOPe1nkl / SUPFAM
OPM superfamily76
OPM protein1sn6

The Saposin-B domains also occur in other proteins, most of them playing a role in interacting with membranes.[2][3][4]

Classification

The saposin (SapB1-SapB2) domains are found in a wide range of proteins. Each half-domain encodes two alpha helices in the SapB domain for a total of four.[5]

The mamallian prosaposin (domain organization below) is a prototypic family member. It also includes the N- and C-terminal SapA domains, both of which are proteolyticly cleaved as the proprotein matures. Four connected pairs of SapB1-SapB2 domains are released, sequentially named Saposin-A through D. Some closely related proteins, such as PSAPL1 and SFTPB, share the architecture and the cleaving mechanism in whole or in part. While Prosaposin and PSAPL1 act in lysosomal lipid degradation, SFTPB is released into the pulmonary surfactant, playing a role in rearranging lipids.[6]

primary structure schematic of prosaposin.

However, proteins like GNLY and AOAH do not carry a SapA domain. While GNLY is essentially a SapB with N-terminal extensions specialized for lysing pathogen cell membranes,[7] the ADAH protein uses the uncleaved SapB domain for targeting the correct intracellular compartment.[8]

The plant-specific insert is an unusual variation on the SapB domains. It features a circular permutation compared to the usual topology: instead of featuring a SapB1-SapB2 unit, it is made up of a SapB2-linker-SapB1 unit seemingly derived by taking a half of each of two SapB units.[5]

Human proteins containing this domain
gollark: We use a few countable infinities of them as workers, although some need the existential horror neural pathways damped a lot.
gollark: Happily, this also avoids issues with ordering effects.
gollark: Oh, obviously you would use a GTech™ nondestructive neural scanning array and spin up an instance of yourself to evaluate each.
gollark: Do you not have arbitrarily fast computers?
gollark: Why would you need *that*?

References
  1. PDB: 2qyp​, Rossmann M, Schultz-Heienbrok R, Behlke J, Remmel N, Alings C, Sandhoff K, Saenger W, Maier T (May 2008). "Crystal structures of human saposins C and D: implications for lipid recognition and membrane interactions". Structure. 16 (5): 809–17. doi:10.1016/j.str.2008.02.016. PMID 18462685.
  2. Munford RS, Sheppard PO, O'Hara PJ (August 1995). "Saposin-like proteins (SAPLIP) carry out diverse functions on a common backbone structure". Journal of Lipid Research. 36 (8): 1653–63. PMID 7595087.
  3. Ponting CP (February 1994). "Acid sphingomyelinase possesses a domain homologous to its activator proteins: saposins B and D". Protein Science. 3 (2): 359–61. doi:10.1002/pro.5560030219. PMC 2142785. PMID 8003971.
  4. Tschopp J, Hofmann K (March 1996). "Cytotoxic T cells: more weapons for new targets?". Trends in Microbiology. 4 (3): 91–4. doi:10.1016/0966-842X(96)81522-8. PMID 8868085.
  5. Ponting CP, Russell RB (May 1995). "Swaposins: circular permutations within genes encoding saposin homologues". Trends in Biochemical Sciences. 20 (5): 179–80. doi:10.1016/S0968-0004(00)89003-9. PMID 7610480.
  6. Hawgood S, Derrick M, Poulain F (Nov 1998). "Structure and properties of surfactant protein B". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1408 (2–3): 150–60. doi:10.1016/S0925-4439(98)00064-7. PMID 9813296.
  7. Anderson DH, Sawaya MR, Cascio D, Ernst W, Modlin R, Krensky A, Eisenberg D (2003). "Granulysin crystal structure and a structure-derived lytic mechanism". J. Mol. Biol. 325 (2): 355–365. CiteSeerX 10.1.1.327.5540. doi:10.1016/S0022-2836(02)01234-2. PMID 12488100.
  8. Staab JF, Ginkel DL, Rosenberg GB, Munford RS (1994). "A saposin-like domain influences the intracellular localization, stability, and catalytic activity of human acyloxyacyl hydrolase". J. Biol. Chem. 269 (38): 23736–42. PMID 8089145.

Further reading
This article incorporates text from the public domain Pfam and InterPro: IPR008138
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