The following text describes a protein:
Function:
Histatins are cationic and histidine-rich peptides mainly found in the saliva of higher primates. They are considered to be major precursors of the protective proteinaceous structure on tooth surfaces (enamel pellicle). Hsts can be divided into two major groups according to their biological functions: antimicrobial Hsts (e.g. Hst 5/HTN3) and cell-activating Hsts (e.g. Hst 1/HTN1, Hst 2/HTN1 and Hst 3/HTN3); [Histatin-3]: Histatin 3 (Hst 3) is mostly involved in cell migration and wound healing in the oral cavity. Also stimulates cell proliferation after binding to heat shock protein HSC70, which enhances HSC70-CDKN1B complex formation and subsequent ubiquitination during G1/S transition. Also displays antifungal activity against pathogenic yeast Candida albicans, however with less effectiveness than Hst 5; [His3-(20-43)-peptide]: Histatin 5 (Hst 5), a fragment of Hst 3, is the major histatin exhibiting antifungal and antibacterial activities. It is effective against pathogenic yeast C.albicans, C.neoformans, C.glabrata and S.cerevisiae as well as ESKAPE bacterial pathogens. Secreted Hst 5 mediates a multi-step intracellular mechanism of action against the pathogen. Depending on peptide concentration and pathogen, uptake across the membrane can occur through transporters, direct interaction with plasma membrane and/or receptor-mediated endocytosis. Binds C.albicans cell wall proteins SSA1 and SSA2 and glycans in an energy-independent manner, then is taken up by the cells through fungal polyamine transporters DUR3 and DUR31 in an energy-dependent manner. Internalized Hst5 is then targeted to the energized mitochondrion to induce reactive oxygen species (ROS) formation and subsequent release of intracellular non-lytic ATP which ultimately leads to fungal cell death. In addition, inhibits C.albicans TRK1 potassium-transporter which causes exudation of intracellular K(+), generating an osmotic imbalance leading to delayed membrane lysis and cell death. Also acts as a potent inhibitor of bacterial proteases such as Lys-gingipain and Arg-gingipain (rgpB) from P.gingivalis as well as human metalloproteases MMP2 and MMP9. The binding of metals such as zinc, copper or nickel with Hst 5 results in the protection of the enamel and antimicrobial activities such as the inhibition of microbial growth by decreasing the metal concentration, the formation of ROS commonly associated with redox-active metals, the induction of membrane disruption mediated by zinc binding. Also involved in coating oral surfaces in the form of a salivary film which reduces colonization by C.albicans on epithelial cell surfaces. Secreted Hst 5 can also internalize mammalian epithelial cells and target the mitochondria although it does not exert cytotoxic effects in these cells. In contrast with Hst 3, not able to promote wound healing in mammalian host cells.
Miscellaneous:
MISCELLANEOUS: The recommended nomenclature of salivary peptides follows published guidelines. In agreement with the authors, it has been decided to indicate the boundaries of the peptides according to the positions within the precursor, and not in the mature protein, as has formerly been proposed; MISCELLANEOUS: [His3-(20-43)-peptide]: Proteolytically cleaved by C. albicans SAP proteases with the decreased cleavage rate order of SAP2>SAP9>SAP3>SAP7>SAP4>SAP1>SAP8, leading to Hst 5 degradation and antifungal activity inactivation. Histatin 1, histatin 3 and histatin 5 constitute more than 80% of the total histatin concentration (Probable).
Subcellular Localization:
Secreted. Note=Secreted by serous acinar and demilune cells; [His3-(20-43)-peptide]: Secreted. Mitochondrion. Note=Targeted to mitochondria in pathogen cells after internalization. Also localized in the vacuole in pathogen cells. Also co-localized with mitochondria after internalization in host mammalian cells.
Domain:
[His3-(20-43)-peptide]: The ATCUN motif mediates Cu(2+) binding and the Bis-His motif mediates Cu(1+) binding and are necessary for antifungal activity. The HExxH motif mediates binding to Zin(2+) which is important for the stabilization of a helical conformation in a hydrophobic environment, Hst5 dimerization and antifungal activity.
Sequence:
MKFFVFALILALMLSMTGADSHAKRHHGYKRKFHEKHHSHRGYRSNYLYDN