1.C.104 The Heterokaryon Incompatibility Prion/Amyloid Protein (HET-s) Family The HET-s protein from the filamentous fungus, Podospora anserina, is a prion involved in a cell death reaction termed heterokaryon incompatibility. This reaction is observed at the point of contact between two genetically distinct strains when one harbors a HET-s prion (in the form of amyloid aggregates) and the other expresses a soluble HET-S protein (96% identical to HET-s). How the HET-s prion interaction with HET-S brings about cell death remains unknown. However, this interaction leads to a relocalization of HET-S from the cytoplasm to the cell periphery, and this change is associated with cell death. A non-toxic HET-s prion converts a soluble HET-S protein into an integral membrane protein that destabilizes membranes (Seuring et al. 2012). Liposomal membrane defects of approximately 10 up to 60 nm in size in transmission electron microscopy images of freeze-fractured proteoliposomes formed in mixtures of HET-S and HET-s amyloids. In liposome leakage assays, HET-S has an innate ability to associate with and disrupt lipid membranes, and this activity is greatly enhanced when HET-S is exposed to HET-s amyloids. HET-s induces the prion-forming domain of HET-S to adopt the β-solenoid fold (previously observed in HET-s), and this change disrupts the globular HeLo domain. Thus, upon interaction with a HET-s prion, the HET-S HeLo domain partially unfolds, exposing a previously buried ∼34-residue N-terminal transmembrane segment. The liberation of this segment targets HET-S to the membrane where it further oligomerizes, leading to a loss of membrane integrity. HET-S thus displays features that are reminiscent of pore-forming toxins (Seuring et al., 2012).
This family belongs to the Ankyrin Repeat Domain-containing (Ank) Superfamily.
References:
Seuring, C., J. Greenwald, C. Wasmer, R. Wepf, S.J. Saupe, B.H. Meier, and R. Riek. (2012). The mechanism of toxicity in HET-S/HET-s prion incompatibility. PLoS Biol 10: e1001451.
Examples:
TC#	Name	Organismal Type	Example
1.C.104.1.1	*The heterokaryon incompatibility prion/amyloid protein, HET-s (Seuring et al., 2012).*	Fungi	*HET-s of Podospora anserina* (Q03689)**

1.C.104.1.2	*Ankyrin repeat domain-containing protein 52, ARDP52 (Seuring et al., 2012).*	Fungi	*ARDP52 of Colletotrichum gloeosporioides* (L2GCS0)**

1.C.104.1.3	Uncharacterized protein of 277 aas		UP of Baudoinia panamericana

1.C.104.1.4	Heterokaryon incompatibility protein S of 298 aa		Protein S of Penicillium subrubescens

1.C.104.1.5	Uncharacterized protein of 729 aas.		UP of Pezoloma ericae

1.C.104.1.6	Uncharacterized protein of 289 aas		UP of Tolypocladium paradoxum

1.C.104.1.7	Uncharacterized protein of 1134 aas with 1 or 2 N-terminal TMSs plus 1 or more central TMSs. The domain homologous to other members of TC# 1.C.104 is N-terminal.		UP of Scedosporium apiospermum

Examples:
TC#	Name	Organismal Type	Example
1.C.104.2.1	Uncharacterized protein of 538 aas		UP of Oidiodendron maius

1.C.104.2.2	Uncharacterized protein of 559 aas		UP of Fusarium oxysporum

1.C.104.2.3	Small s-like protein of 206 aas		Small s protein of Colletotrichum fructicola

1.C.104.2.4	Uncharacterized protein of 1067 aas and 1 or 2 N-terminal TMSs. The domain corresponding to TC# 1.C.104 is N-terminal, and a C-terminal domain is a protein kinase domain.		UP of Byssochlamys spectabilis

1.C.104.2.5	Uncharacterized protein of 436 aas		UP of Glarea lozoyensis

Examples:
TC#	Name	Organismal Type	Example
1.C.104.3.1	Uncharacterized protein of 414 aas		UP of Venturia inaequalis

1.C.104.3.2	Uncharacterized protein of 462 aas and 1 N-terminal TMS.		UP of Pseudocercospora fijiensis

Examples:
TC#	Name	Organismal Type	Example