Phosphatidylinositol 3-phosphate-binding protein 2 (Pib2) is a yeast protein involved in the regulation of TORC1 signaling and lysosomal membrane permeabilization. It is essential for the reactivation of TORC1 following exposure to

rapamycin Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ rejection, organ transplant rejection, treat a rare lung disease called lymphang ...

or nutrient starvation.

Discovery

Pib2 was first identified as a FYVE domain-containing protein able to bind

phosphatidylinositol 3-phosphate Phosphatidylinositol 3-phosphate (PI3P) is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and III phosph ...

(PI3P). Pib2 was later identified in a screen for rapamycin sensitivity, along with several other TORC1 regulatory proteins (including Ego1, Gtr1, Gtr2, and other key TORC1 related proteins).

Structure

Pib2 is a 70.6 kDa protein with 635 amino acids (Uniprot - P53191). Pib2 has 5 weakly conserved motifs among

fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...

and 2 universally conserved motifs. The partially conserved motifs are found in the

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

region of the protein and are generally referred to as regions A-E The universally conserved motifs include a phosphatidylinositol-3-phosphate (PI3P)-binding

FYVE domain In molecular biology the FYVE zinc finger domain is named after the four cysteine-rich proteins: Fab 1 (yeast orthologue of PIKfyve), YOTB, Vac 1 (vesicle transport protein), and EEA1, in which it has been found. FYVE domains bind phosphatidyli ...

, and a short tail motif at the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

Mammalian homologs

Pib2 has 2 mammalian homologs, Phafin1 (also known as LAPF or PLEKHF1) and Phafin2 (EAPF or PLEKHF2). The phafin proteins each have a PH (pleckstrin homology) domain and

. Phafin1 also has a tail motif similar to that of Pib2. These proteins have not been shown to be involved in the regulation of mammalian TORC1 signaling but have been shown to be involved in related processes.

Function

TORC1 regulation

In ''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...

'', Pib2 has been shown to be involved in regulating TORC1 signaling. Pib2 is found at the yeast

vacuole A vacuole () is a membrane-bound organelle which is present in Plant cell, plant and Fungus, fungal Cell (biology), cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water ...

and

endosomes Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...

. The PI3P binding

of Pib2 is key for this localization. Pib2 also interacts with some TORC1 components, including Kog1 and Tor1, and has been shown to be necessary for TORC1 reactivation following inhibition by rapamycin or nutrient starvation. Additionally, Pib2 is essential for TORC1 reactivation by stimulation with

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-Car ...

and

glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...

. In terms of TORC1 reactivation, it has been observed that Pib2 can have both a positive and negative effect. The

of Pib2 is key for TORC1 reactivation, whereas the

region has an inhibitory effect on TORC1 reactivation.

Lysosomal membrane permeabilization

Lysosomal membrane permeabilization (LMP) is a process which is important for inducing cell death in a range of animals and plants. LMP also occurs in ''

'' during

sporulation In biology, a spore is a unit of sexual (in fungi) or asexual reproduction that may be adapted for dispersal and for survival, often for extended periods of time, in unfavourable conditions. Spores form part of the life cycles of many plant ...

. Pib2 has been implicated in the regulation of this process in stressed yeast through the promotion of TORC1 activity.

References

{{Reflist Saccharomyces cerevisiae genes Fungal proteins