9.B.149 The M50 Peptidase (M50-P) Family

The M50 Peptidase (S2P-M50) family includes proteins frequently of 700-800 aas in length with six N-terminal or centrally located TMSs. However, other members of the family are relatively small (300-400 aas).  They are integral membrane zinc metaloprotease that cleave transmembrane domains in proteins. They are frequently encoded in gene clusters with lantibiotic biosynthetic enzymes and ABC transporters. For example, Streptomyces griseus encodes in the following order: an ABC-2 type transporter, an ABC-type ATPase (see TC#3.A.1.105.11), a S2P-M50 peptidase with a CBS domain (see 9.B.149.1.1), a lantibiotic synthesis protein and a lantibiotic dehydratase. Other M50 peptidases include Membrane Fusion Protein (MFP; TC# 8.A.1) domains or may have an MFP encoded in the same operon. Still others include ABC-type ATPase domains fused to them, indicating a close relationship with the transporter. Peptidase processing of bacteriocins is known in some cases to occur during transport, and the peptidase and transporter presumably form a complex in the membrane. Many bacteriocin-producing Gram-positive bacteria have ABC exporters that function with an essential MFP (Harley et al. 2000). 

This family belongs to the .



Harley, K.T., G.M. Djordjevic, T.T. Tseng, and M.H. Saier. (2000). Membrane-fusion protein homologues in gram-positive bacteria. Mol. Microbiol. 36: 516-517.

Yu, Y.T. and L. Kroos. (2000). Evidence that SpoIVFB is a novel type of membrane metalloprotease governing intercompartmental communication during Bacillus subtilis sporulation. J. Bacteriol. 182: 3305-3309.


TC#NameOrganismal TypeExample

Peptidase M50 with CBS domain


M50 peptidase of Streptomyces griseus (B1W279)


Uncharacterized protein of 525 aas and 8 TMSs


Thermoplasma volcanium (Q97BX9)


Putative Zn-dependent protease of 220 aas

Protease of Bdellovibrio bacteriovorus


Sporulation stage IV FB protein, SpoIVFB, 288 aas and 5 TMSs 

SpoIVFB of Bacillus jeotgali


Integral membrane protease, SpoIVFB or BofB, of 288 aas and 5 or 6 TMSs (Yu and Kroos 2000).

SpoIVFB of Bacillus subtilis


S2P-M50-like protein with C-terminal ABC ATPase domain.  The 6 TMS bundle shows sequence similarity with members 15, 4 and 5 of this 9.B.149 family  but may lack the M50 peptidase domain. It may therefore be an ABC transporter, but this has not been demonstrated.  The complete protein shows greatest sequence similarity with ABC (ATPase) proteins of the family with TC# 3.A.1.105.


Membrane protein with C-terminal ATPase domain of Catenulispora acidiphila (C7QI22)


S2P-M50-like peptidase with C-terminal ABC ATPase. In a lantibiotic synthesis gene cluster. The 6 TMS bundle shows sequence similarity with members 14, 4 and 5 of this 9.B.149 family but may lack the M50 peptidase domain.  It may therefore be an ABC transporter, but this has not been demonstrated.  The complete protein shows greatest sequence similarity with ABC (ATPase) proteins of the family with TC# 3.A.1.105.


M50 peptidase-like protein of Catenulispora acidiphila (C7QBX7)


Uncharacterized protease-like protein with 755 aas and 9 TMSs in a 6 + 3 TMS arrangement.  The C-terminal hydrophilic domain and the last TMS resemble the N-terminal parts of membrane fusion proteins (TC# 8.A.1).

UP of Gemmata obscuriglobus


Zinc metalo-protease of 383 aas and 6 TMSs

Protease of Amycolatopsis mediterranei (Nocardia mediterranei)


M50 peptidase with 8 putative TMSs and a sequence divergent C-terminal Membrane Fusion Protein (MFP) domain


M50 peptidase of Rhodopirellula baltica (F2AL16)


M50 family peptidase (720aas). In a gene cluster with an MFP (Q3AQQ8) and a putative phytochrome sensor with a GAF domain followed by an MFP domain at the C-terminus (631aas; Q3AQQ9)


M50 peptidase of Chlorobium chlorochromalii (Q3AQR0)


M50 peptidase (Zn2+-metalopeptidase) of 392 aas and 6TMSs. In a gene cluster with an ABC transporter of 6TMSs with a CBS domain (F8D412) and an ABC ATPase (F8D413) (3.A.1.105.12)


M50 peptidase of Halopiger xanaduensis (F8D414)


Uncharacterized protein of 934 aas and 6-7 TMSs

Alveolata (ciliates)

UP of Perkinsus marinus


Uncharacterized protein of 199 aas and 6 TMSs


UP of Methanothermobacter thermautotrophicus


Uncharacterized protein of 373 aas and 8 TMSs


UP of Pyrococcus horikoshii


TC#NameOrganismal TypeExample

Regulator of σW transmembrane metaloprotease, RasP (YluC) of 422 aas and 4 - 6 TMSs. RasP, when defective, causes defects in competence development, protein secretion and membrane protein production (Zweers et al. 2012). σV activation in B. subtilis is controlled by regulated intramembrane proteolysis and requires RasP (Hastie et al. 2013). RasP also cleaves both of the stress response anti-sigma factors, RsiW and RsiV, as well as the cell division protein FtsL, and remnant signal peptides, within their transmembrane segments (Parrell et al. 2017).

RasP of Bacillus subtilis


Membrane metaloprotease of 343 aas and 4-6 TMSs.

Protease of Candidatus Wolfebacteria bacterium