In molecular biology, the Signal Peptide Peptidase (SPP) is a type of protein that specifically cleaves parts of other proteins. It is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in adjacent

transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid b ...

s (TMDs). Its sequences is highly conserved in different vertebrate species. SPP

cleave Cleave may refer to: *Cleave (surname) *Cleave (fiber), a controlled break in optical fiber *RAF Cleave, was an airfield in the north of Cornwall, England, May 1939 - Nov 1945 *The process of protein cleaving as a form of post-translational modifi ...

s remnant

signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-ter ...

s left behind in membrane by the action of

signal peptidase Signal peptidases are enzymes that convert secretory and some membrane proteins to their mature or pro forms by cleaving their signal peptides from their N-termini. Signal peptidases were initially observed in endoplasmic reticulum (ER)-deri ...

and also plays key roles in

immune In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...

surveillance and the maturation of certain

viral protein A viral protein is both a component and a product of a virus. Viral proteins are grouped according to their functions, and groups of viral proteins include structural proteins, nonstructural proteins, regulatory proteins, and accessory proteins. ...

Biological function

Physiologically SPP processes signal peptides of classical

MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on ...

preproteins. A nine amino acid-long cleavage fragment is then presented on HLA-E receptors and modulates the activity of

natural killer cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represe ...

. SPP also plays a pathophysiological role; it cleaves the structural nucleocapsid protein (also known as core protein) of the

Hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, ...

virus and thus influences viral reproduction rate. In mice, a nonamer peptide originating from the SPP protein serves as minor histocompatibility antigen

HM13 Minor histocompatibility antigen H13 is a protein that in humans is encoded by the ''HM13'' gene. Function The minor histocompatibility antigen 13 is a nonamer peptide that originates from a protein encoded by the ''H13'' gene. The peptide is ...

that plays a role in

transplant rejection Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient ...

The homologous proteases

SPPL2A Signal peptide peptidase-like 2A, also known as SPPL2A, is a human gene. Function This gene is a member of the signal peptide peptidase-like protease (SPPL) family and encodes a lysosomal/late endosomal membrane protein with the conserved acti ...

and

SPPL2B Signal peptide peptidase-like 2B, also known as SPPL2B, is a human gene. This gene is a member of the signal peptide peptidase-like protease (SPPL) family with the conserved active site motifs 'YD' and 'GxGD' in adjacent transmembrane domains (TM ...

promote the intramembrane cleavage of

TNFα Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

in activated

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...

and might play an immunomodulatory role. For SPPL2c and SPPL3 no substrates are known. SPPs do not require

cofactors Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the orde ...

as demonstrated by expression in

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

and purification of a proteolytically active form. The C-terminal region defines the functional domain, which is in itself sufficient for

proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases ...

activity.

Type IV leader peptidase

Another family of signal aspartic endopeptidases was found in bacteria.

Bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

produce a number of protein precursors that undergo post-translational

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

and

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

prior to

secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classica ...

as active proteins. Type IV prepilin leader peptidases are enzymes that mediate this type of

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...

. Type IV pilin is a protein found on the surface of ''

Pseudomonas ''Pseudomonas'' is a genus of Gram-negative, Gammaproteobacteria, belonging to the family Pseudomonadaceae and containing 191 described species. The members of the genus demonstrate a great deal of metabolic diversity and consequently are able ...

aeruginosa'', ''Neisseria gonorrhoeae'' and other Gram-negative pathogens. Pilin subunits attach the infecting

organism In biology, an organism () is any life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), taxonomy into groups such as Multicellular o ...

to the surface of host

epithelial cell Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...

s. They are synthesised as prepilin subunits, which differ from mature pilin by virtue of containing a 6-8 residue leader peptide consisting of charged amino acids. Mature type IV pilins also contain a

methylated In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These te ...

N-terminal

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

residue. The bifunctional enzyme prepilin peptidase (PilD) from ''Pseudomonas aeruginosa'' is a key determinant in both type-IV

pilus A pilus (Latin for 'hair'; plural: ''pili'') is a hair-like appendage found on the surface of many bacteria and archaea. The terms ''pilus'' and '' fimbria'' (Latin for 'fringe'; plural: ''fimbriae'') can be used interchangeably, although some ...

biogenesis Spontaneous generation is a superseded scientific theory that held that living creatures could arise from nonliving matter and that such processes were commonplace and regular. It was hypothesized that certain forms, such as fleas, could arise ...

and

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

protein secretion, in its roles as a leader peptidase and methyl transferase (MTase). It is responsible for endopeptidic cleavage of the unique leader

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s that characterise type-IV pilin precursors, as well as

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

s with

homologous Homology may refer to: Sciences Biology *Homology (biology), any characteristic of biological organisms that is derived from a common ancestor *Sequence homology, biological homology between DNA, RNA, or protein sequences * Homologous chrom ...

leader sequences that are essential components of the general secretion pathway found in a variety of Gram-negative

pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ger ...

s. Following removal of the leader peptides, the same enzyme is responsible for the second

posttranslational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...

that characterises the type-IV pilins and their homologues, namely N-methylation of the newly exposed N-terminal

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

residue.

References

External links

* The

MEROPS MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibi ...

online database for peptidases and their inhibitors: SP
A22.003
SPPL2a
A22.007
SPPL2
A22.004
SPPL2
A22.006
SPPL
A22.005
* - Calculated spatial position of type 1 signal peptidase in membrane * {{Portal bar, Biology, border=no Integral membrane proteins Protein targeting Hydrolases Proteases EC 3.4.23

Biological function

Type IV leader peptidase

See also

References

Further reading

External links