1.C.113.  The Hemolysin III (Hly III) Family

The Hly III family (SwissProt family UPF0073) consists of proteins of 200-250 residues with 7 putative TMSs. They are from bacteria and eukaryotes (both plants and animals). One is a characterized hemolysin from Bacillus cereus. Another is a protein induced during differentiation of monocytes to macrophage in humans.

Bacillus cereus hemolysin III activity has been tested in crude extracts, and from Escherichia coli carrying the hly-III gene (Baida and Kuzmin 1996). It was concluded that hemolysin III is a pore-forming hemolysin with functional pore diameter of about 3-3.5 nm. Hemolysis occurs in at least three steps: (i) the temperature-dependent binding of the Hly-III monomers to the erythrocyte membrane; (ii) the temperature-dependent formation of the transmembrane oligomeric pore, and (iii) the temperature-independent erythrocyte lysis.

One homologue is a receptor for ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism (Tanabe et al. 2015, Yamauchi et al. 2003). Required for normal glucose and fat homeostasis and for maintaining normal body weight. ADIPOQ-binding activates a signaling cascade that leads to increased AMPK activity, and ultimately to increased fatty acid oxidation, increased glucose uptake and decreased gluconeogenesis. This receptor has high affinity for globular adiponectin and low affinity for full-length adiponectin.  The relationship between this receptor and the hemolysins is not clear, but they are definitely homologous with the same general topology.


 

References:

Baida, G.E. and N.P. Kuzmin. (1995). Cloning and primary structure of a new hemolysin gene from Bacillus cereus. Biochim. Biophys. Acta. 1264: 151-154.
Baida, G.E. and N.P. Kuzmin. (1996). Mechanism of action of hemolysin III from Bacillus cereus. Biochim. Biophys. Acta. 1284: 122-124.
Góñez, L.J., G. Naselli, I. Banakh, H. Niwa, and L.C. Harrison. (2008). Pancreatic expression and mitochondrial localization of the progestin-adipoQ receptor PAQR10. Mol Med 14: 697-704.
Hafiane, A., K. Gasbarrino, and S.S. Daskalopoulou. (2019). Adiponectin and cholesterol efflux. Metabolism 153953. [Epub: Ahead of Print]
Lee, Y., A. Nakano, S. Nakamura, K. Sakai, M. Tanaka, K. Sanematsu, N. Shigemura, and T. Matsui. (2021). In vitro and in silico characterization of adiponectin-receptor agonist dipeptides. NPJ Sci Food 5: 29.
Miller, E.N., L.R. Jarboe, L.P. Yomano, S.W. York, K.T. Shanmugam, and L.O. Ingram. (2009). Silencing of NADPH-dependent oxidoreductase genes (yqhD and dkgA) in furfural-resistant ethanologenic Escherichia coli. Appl. Environ. Microbiol. 75: 4315-4323.
Pang, Y., J. Dong, and P. Thomas. (2013). Characterization, neurosteroid binding and brain distribution of human membrane progesterone receptors δ and {epsilon} (mPRδ and mPR{epsilon}) and mPRδ involvement in neurosteroid inhibition of apoptosis. Endocrinology 154: 283-295.
Petersen, S.L., K.A. Intlekofer, P.J. Moura-Conlon, D.N. Brewer, J. Del Pino Sans, and J.A. Lopez. (2013). Nonclassical progesterone signalling molecules in the nervous system. J Neuroendocrinol 25: 991-1001.
Rehli, M., S.W. Krause, L. Schwarzfischer, M. Kreutz, and R. Andreesen. (1995). Molecular cloning of a novel macrophage maturation-associated transcript encoding a protein with several potential transmembrane domains. Biochem. Biophys. Res. Commun. 217: 661-667.
Tanabe, H., Y. Fujii, M. Okada-Iwabu, M. Iwabu, Y. Nakamura, T. Hosaka, K. Motoyama, M. Ikeda, M. Wakiyama, T. Terada, N. Ohsawa, M. Hato, S. Ogasawara, T. Hino, T. Murata, S. Iwata, K. Hirata, Y. Kawano, M. Yamamoto, T. Kimura-Someya, M. Shirouzu, T. Yamauchi, T. Kadowaki, and S. Yokoyama. (2015). Crystal structures of the human adiponectin receptors. Nature 520: 312-316.
Vasiliauskaité-Brooks, I., R. Sounier, P. Rochaix, G. Bellot, M. Fortier, F. Hoh, L. De Colibus, C. Bechara, E.M. Saied, C. Arenz, C. Leyrat, and S. Granier. (2017). Structural insights into adiponectin receptors suggest ceramidase activity. Nature. [Epub: Ahead of Print]
Wunderlich, J. (2022). Updated List of Transport Proteins in. Front Cell Infect Microbiol 12: 926541.
Yamauchi, T., J. Kamon, Y. Ito, A. Tsuchida, T. Yokomizo, S. Kita, T. Sugiyama, M. Miyagishi, K. Hara, M. Tsunoda, K. Murakami, T. Ohteki, S. Uchida, S. Takekawa, H. Waki, N.H. Tsuno, Y. Shibata, Y. Terauchi, P. Froguel, K. Tobe, S. Koyasu, K. Taira, T. Kitamura, T. Shimizu, R. Nagai, and T. Kadowaki. (2003). Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423: 762-769.
Examples:

TC#NameOrganismal TypeExample
1.C.113.1.1The Hly III protein Bacteria Hly III of Bacillus cereus
 
1.C.113.1.10

YqfA protein of unknown function.  It may play a role in furfural resistance (Miller et al. 2009).

YqfA of E. coli

 
1.C.113.1.11

ADIPOR2 of 387 aas and 7 TMSs.  It may funtion in promoting cholesterol efflux together with ADIPOR1 and adiponectin (Hafiane et al. 2019).

Adiponectin receptor 2, ADIPOR2, of Homo sapiens

 
1.C.113.1.12

Progestin (P4) receptor beta of 354 aas and 8 TMSs.  It couples to G proteins (Petersen et al. 2013). It seems to act through a Gi mediated pathway and may be involved in oocyte maturation (Petersen et al. 2013). Also binds dehydroepiandrosterone (DHEA), pregnanolone, pregnenolone and allopregnanolone (Pang et al. 2013).

Progesterone receptor of Homo sapiens

 
1.C.113.1.2

Hemolysin III-like protein of 229 aas

Spirochaetes

Hemolysin III-like protein of Borrelia miyamotoi

 
1.C.113.1.3

Hemolysin D channel protein of the hemolysin III family

Proteobacteria

Hemolysin D of Pseudomonas stutzeri

 
1.C.113.1.4

Hemolysin III of 205 aas

Deinococcus/Thermus

Hemolysin of Thermus thermophilus

 
1.C.113.1.5

Hemolysin III-like protein of 407 aas

Algae

Hemolysin of Galdieria sulphuraria (Red alga)

 
1.C.113.1.6

Putative hemolysin III of 262 aas

Actinobacteria

Hemolysin of Corynebacterium diphtheriae

 
1.C.113.1.7

Hemolysin of 282 aas, HlyIII; forms pores of ~3.2 nm for solutes and ions (Wunderlich 2022).

Alveolata

Hemolysin of Plasmodium falciparum

 
1.C.113.1.8

Adiponectin receptor  protein of 340 aas

Euglenozoa

Adiponectin receptor of Trypanosoma cruzi

 
1.C.113.1.9

The adiponectin receptor 1 or ADIPOQ, an essential hormone secreted by adipocytes that regulates glucose and lipid metabolism (Tanabe et al. 2015; Yamauchi et al. 2003. Required for normal glucose and fat homeostasis and for maintaining a normal body weight. ADIPOQ-binding activates a signaling cascade that leads to increased AMPK activity, and ultimately to increased fatty acid oxidation, increased glucose uptake and decreased gluconeogenesis. Has high affinity for globular adiponectin and low affinity for full-length adiponectin. The 3-d structure revealed ceramidase activity for both ADIPOR1 and ADIPOR2; however, the two structures are substantially different (Vasiliauskaité-Brooks et al. 2017).  It may function with adiponectin to stimulate cholesterol efflux via ABCA1 (Hafiane et al. 2019). The Tyr-Pro dipeptide may function as an AdipoR1 agonist (Lee et al. 2021).

 

Animals

ADIPOR1 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
1.C.113.2.1The monocyte to macrophage differentiation protein (MMDP) Animals MMDP of Homo sapiens
 
1.C.113.2.2
Monocyte to macrophage differentiation factor 2 of 363 aas and 7 TMSs

Animals

Hemolysin homologue of Culex quinquefasciatus (Southern house mosquito) (Culex pungens)

 
1.C.113.2.3

Progestin and adipoQ receptor family member 10, PAQR10, of 270 aas and 7 TMSs.  Also called Monocyte to macrophage differentiation factor 2, MMD2. PAQR10 is structurally related to some bacterial hemolysins, pore-forming virulence factors that target mitochondria and regulate apoptosis (Góñez et al. 2008).

PAQR10 of Homo sapiens