Lon protease homolog, mitochondrial is a protease, an enzyme that in humans is encoded by the LONP1 gene. [5] [6] [7] [8]
Lon protease homolog, mitochondrial is a protease, an enzyme that in humans is encoded by the LONP1 gene. [5] [6] [7] [8]
The nuclear-gene encoded mitochondrial matrix LON peptidase 1 (LONP1), originally thought to be responsible for protein quality control (PQC) by degrading unfolded or misfolded proteins, has several essential functions like proteolytic activity, chaperone activity and mitochondrial DNA (mtDNA) regulation. Lon protease is a member of ATP-dependent proteases (AAA+ proteases). Mature LONP1 is catalytically active in its homohexameric structure, while other formations of complexes have been observed such as the homoheptameric ring in Saccharomyces cerevisiae . A single subunit of LONP1 consists of three domains: The N-domain for substrate recognition and binding, an AAA + module (A-domain) for ATP binding and hydrolysis, and a P-domain for protein proteolysis. A homologous protease to LONP1 expressed in E.coli. regulates gene expression by targeting specific regulatory proteins for degradation. Moreover, LONP1 is able to bind a specific sequence in the light and heavy chain promoters of the mitochondrial genome which are involved in regulation of mtDNA replication and transcription. [7]
Lon protease (LONP1) is a conserved serine peptidase identified from bacteria to eukaryotic cells. [9] In mitochondrial matrix, a majority of damaged proteins is removed via proteolysis led by Lon protease, which is an essential mechanism for mitochondrial protein quality control. LONP1 is the major protease responsible for the recognition and removal of unfolded proteins in the mitochondrial matrix and thereby protects the cell from the accumulation of aggregated proteins in the mitochondrion. [10] However LONP1 is unable to recognise or degrade model aggregated proteins.
For Lon protease-dependent degradation, protein substrates are first recognized and then unfolded if necessary in an ATP-dependent manner. The substrates are subsequently transferred through the pore of complex and into the proteolytic chamber of complex for degradation. ATP binding to the AAA module of the Lon complex results in a change in Lon conformation into a proteolytically active state. In general, Lon protease interacts with peptide regions(sequences) that are located within the hydrophobic core of substrates and rarely on the surface. These regions can be presented to Lon protease when proteins are damaged and lost their conformation integrity. [11] In addition to misfolded proteins, several regulatory proteins can be processed by Lon protease by removing a degradable tag before they fully gain their biological functions. [12]
LONP1 is also a DNA-binding protein that participates in mtDNA maintenance and gene expression regulation. [13] LONP1 degrades mitochondrial transcription factor A (TFAM) when substrate is modified by post-translational modifications (PTMs) such as phosphorylation, regulating mtDNA copy number and metabolism to maintain the TFAM/mtDNA ratio necessary to control replication and transcription. [14]
Given the crucial role of LON protease in maintaining the control of mitochondrial function, [15] its dynamics in expression under stress conditions has been found associating with human diseases and aging. [16] [17] For example, LONP1 expression levels are increased in different tumors and tumor cell lines. Downregulation of LONP1 in some tumor cells causes apoptosis and cell death, indicating a possible addiction of tumor cells to LONP1 function, as occurs with other intracellular proteases associated with cancer. In addition, genetic deficiency of LONP1, caused by biallelic deleterious variants in the LONP1 gene, result in a pattern of severe congenital anomalies called the CODAS syndrome [18] [19] for "Cerebral, ocular, dental, auricular, skeletal anomalies. [20] Thus, LONP1 seems to have important functions in developmental processes that had not been predicted from the previous studies in cell culture models. A study published in 2021 has suggested that genetic variants in LONP1 may be a predisposing factor to the development of congenital diaphragmatic hernia. [21] highlighting yet another role of LONP1 in human embryonic/fetal development.
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
AAA proteins or ATPases Associated with diverse cellular Activities are a protein family sharing a common conserved module of approximately 230 amino acid residues. This is a large, functionally diverse protein family belonging to the AAA+ protein superfamily of ring-shaped P-loop NTPases, which exert their activity through the energy-dependent remodeling or translocation of macromolecules.
The heat shock proteins HslV and HslU are expressed in many bacteria such as E. coli in response to cell stress. The hslV protein is a protease and the hslU protein is an ATPase; the two form a symmetric assembly of four stacked rings, consisting of an hslV dodecamer bound to an hslU hexamer, with a central pore in which the protease and ATPase active sites reside. The hslV protein degrades unneeded or damaged proteins only when in complex with the hslU protein in the ATP-bound state. HslV is thought to resemble the hypothetical ancestor of the proteasome, a large protein complex specialized for regulated degradation of unneeded proteins in eukaryotes, many archaea, and a few bacteria. HslV bears high similarity to core subunits of proteasomes.
Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. In addition, Hsp72 also facilitates DNA repair. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.
26S protease regulatory subunit 6A, also known as 26S proteasome AAA-ATPase subunit Rpt5, is an enzyme that in humans is encoded by the PSMC3 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.
Valosin-containing protein (VCP) or transitional endoplasmic reticulum ATPase also known as p97 in mammals and CDC48 in S. cerevisiae, is an enzyme that in humans is encoded by the VCP gene. The TER ATPase is an ATPase enzyme present in all eukaryotes and archaebacteria. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome.
26S protease regulatory subunit 8, also known as 26S proteasome AAA-ATPase subunit Rpt6, is an enzyme that in humans is encoded by the PSMC5 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.
26S protease regulatory subunit 6B, also known as 26S proteasome AAA-ATPase subunit Rpt3, is an enzyme that in humans is encoded by the PSMC4 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.
Hematopoietic lineage cell-specific protein is a protein that in humans is encoded by the HCLS1 gene.
Ras GTPase-activating protein-binding protein 1 is an enzyme that in humans is encoded by the G3BP1 gene.
Pitrilysin metallopeptidase 1 also known as presequence protease, mitochondrial (PreP) and metalloprotease 1 (MTP-1) is an enzyme that in humans is encoded by the PITRM1 gene. It is also sometimes called metalloprotease 1 (MP1).PreP facilitates proteostasis by utilizing an ~13300-A(3) catalytic chamber to degrade toxic peptides, including mitochondrial presequences and β-amyloid. Deficiency of PreP is found associated with Alzheimer’s disease. Reduced levels of PreP via RNAi mediated knockdown have been shown to lead to defective maturation of the protein Frataxin.
ATP-dependent metalloprotease YME1L1 is an enzyme that in humans is encoded by the YME1L1 gene. YME1L1 belongs to the AAA family of ATPases and mainly functions in the maintenance of mitochondrial morphology. Mutations in this gene would cause infantile-onset mitochondriopathy.
ATP-dependent Clp protease proteolytic subunit (ClpP) is an enzyme that in humans is encoded by the CLPP gene. This protein is an essential component to form the protein complex of Clp protease.
Cdc6, or cell division cycle 6, is a protein in eukaryotic cells. It is mainly studied in the budding yeast Saccharomyces cerevisiae. It is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle that coordinate S phase and mitosis. It is part of the pre-replicative complex (pre-RC) and is required for loading minichromosome maintenance (MCM) proteins onto the DNA, an essential step in the initiation of DNA synthesis. In addition, it is a member of the family of AAA+ ATPases and highly related to ORC1; both are the same protein in archaea.
In molecular biology, the Lon protease family is a family of enzymes that break peptide bonds in proteins resulting in smaller peptides or amino acids. They are found in archaea, bacteria and eukaryotes. Lon proteases are ATP-dependent serine peptidases belonging to the MEROPS peptidase family S16. In the eukaryotes the majority of the Lon proteases are located in the mitochondrial matrix. In yeast, the Lon protease PIM1 is located in the mitochondrial matrix. It is required for mitochondrial function, it is constitutively expressed but is increased after thermal stress, suggesting that PIM1 may play a role in the heat shock response. Lon proteases have two specific subfamilies: LonA and LonB, differentiated by the number of AAA+ domains found in the protein.
ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial is an enzyme that in humans is encoded by the CLPX gene. This protein is a member of the family of AAA Proteins and is to form the protein complex of Clp protease.
Metalloendopeptidase OMA1, mitochondrial is an enzyme that in humans is encoded by the OMA1 gene. OMA1 is a Zn2+-dependent metalloendopeptidase in the inner membrane of mitochondria. The OMA1 acronym was derived from overlapping proteolytic activity with m-AAA protease 1.
The mitochondrial unfolded protein response (UPRmt) is a cellular stress response related to the mitochondria. The UPRmt results from unfolded or misfolded proteins in mitochondria beyond the capacity of chaperone proteins to handle them. The UPRmt can occur either in the mitochondrial matrix or in the mitochondrial inner membrane. In the UPRmt, the mitochondrion will either upregulate chaperone proteins or invoke proteases to degrade proteins that fail to fold properly. UPRmt causes the sirtuin SIRT3 to activate antioxidant enzymes and mitophagy.
Lon peptidase 2, peroxisomal is a protein that in humans is encoded by the LONP2 gene.
Alfred Lewis Goldberg was an American cell biologist-biochemist and professor at Harvard University. His major discoveries have concerned the mechanisms and physiological importance of protein degradation in cells. Of wide impact have been his lab's demonstration that all cells contain a pathway for selectively eliminating misfolded proteins, his discoveries about the role of proteasomes in this process and of the enzyme systems catalyzing protein breakdown in bacteria, his elucidating the mechanisms for muscle atrophy and the role of proteasomes in antigen presentation to the immune system, and his introduction of proteasome inhibitors now widely used as research tools and in the treatment of blood cancers.