Myosin Light-Chain kinase, smooth muscle | |||||||
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Identifiers | |||||||
Symbol | MYLK | ||||||
NCBI gene | 4638 | ||||||
HGNC | 7590 | ||||||
OMIM | 600922 | ||||||
RefSeq | NM_053025 | ||||||
UniProt | Q15746 | ||||||
Other data | |||||||
EC number | 2.7.11.18 | ||||||
Locus | Chr. 3 qcen-q21 | ||||||
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myosin light-chain kinase 2, skeletal muscle | |||||||
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Identifiers | |||||||
Symbol | MYLK2 | ||||||
NCBI gene | 85366 | ||||||
HGNC | 16243 | ||||||
OMIM | 606566 | ||||||
RefSeq | NM_033118 | ||||||
UniProt | Q9H1R3 | ||||||
Other data | |||||||
Locus | Chr. 20 q13.31 | ||||||
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myosin light-chain kinase 3, cardiac | |||||||
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Identifiers | |||||||
Symbol | MYLK3 | ||||||
NCBI gene | 91807 | ||||||
HGNC | 29826 | ||||||
OMIM | 612147 | ||||||
RefSeq | NM_182493 | ||||||
UniProt | Q32MK0 | ||||||
Other data | |||||||
Locus | Chr. 16 q11.2 | ||||||
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Human Myosin Light-Chain Kinase | |||||||
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![]() The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156. [2] | |||||||
Identifiers | |||||||
Symbol | MYLK4 | ||||||
NCBI gene | 340156 | ||||||
HGNC | 27972 | ||||||
RefSeq | NM_001012418 | ||||||
UniProt | Q86YV6 | ||||||
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Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II. [3]
While there are numerous differing domains depending on the cell type, there are several characteristic domains common amongst all MYLK isoforms. MYLK’s contain a catalytic core domain with an ATP binding domain. On either sides of the catalytic core sit calcium ion/calmodulin binding sites. Binding of calcium ion to this domain increases the affinity of MYLK binding to myosin light chain. This myosin binding domain is located at the C-Terminus end of the kinase. On the other side of the kinase at the N-Terminus end, sits the actin-binding domain, which allows MYLK to form interactions with actin filaments, keeping it in place. [4] [5]
Four different MYLK isoforms exist: [6]
These enzymes are important in the mechanism of contraction in muscle. Once there is an influx of calcium cations (Ca2+) into the muscle, either from the sarcoplasmic reticulum or from the extracellular space, contraction of smooth muscle fibres may begin. First, the calcium will bind to calmodulin. [7] After the influx of calcium ions and the binding to calmodulin, pp60 SRC (a protein kinase) causes a conformational change in MYLK, activating it and resulting in an increase in phosphorylation of myosin light chain at serine residue 19. The phosphorylation of MLC will enable the myosin crossbridge to bind to the actin filament and allow contraction to begin (through the crossbridge cycle). Since smooth muscle does not contain a troponin complex, as striated muscle does, this mechanism is the main pathway for regulating smooth muscle contraction. Reducing intracellular calcium concentration inactivates MLCK but does not stop smooth muscle contraction since the myosin light chain has been physically modified through phosphorylation(and not via ATPase activity). To stop smooth muscle contraction this change needs to be reversed. Dephosphorylation of the myosin light chain (and subsequent termination of muscle contraction) occurs through activity of a second enzyme known as myosin light-chain phosphatase (MLCP). [8]
Protein kinase C and ROC Kinase are involved in regulating Calcium ion intake; these Calcium ions, in turn stimulate a MYLK, forcing a contraction. [9] Rho kinase also modulates the activity of MYLK by downregulating the activity of MYLK's counterpart protein: Myosin Light Chain Phosphatase (MYLP). [10] In addition to downregulation of MYLK, ROCK indirectly strengthens actin/myosin contraction through inhibiting Cofilin, a protein which depolymerizes actin stress fibers. [11] Similar to ROCK, Protein Kinase C regulates MYLK via the CPI-17 protein, which downregulates MYLP. [12]
Some pulmonary disorders have been found to arise due to an inability of MYLK to function properly in lung cells. Over-activity in MYLK creates an imbalance in mechanical forces between adjacent endothelial and lung tissue cells. An imbalance may result in acute respiratory distress syndrome, in which fluid is able to pass into the alveoli. [13] Within the cells, MYLK provides an inward pulling force, phosphorylating myosin light chain causing a contraction of the myosin/actin stress fiber complex. Conversely, cell-cell adhesion via tight and adherens junctions, along with anchoring to extra cellular matrix (ECM) via integrins and focal adhesion proteins results in an outward pulling force. Myosin light chain pulls the actin stress fiber attached to the cadherin, resisting the force of the adjacent cell's cadherin. However, when the inward pulling force of the actin stress fiber becomes greater than the outward pulling force of the cell adhesion molecules due to an overactive MYLK, tissues can become slightly pulled apart and leaky, leading to passage of fluid into the lungs. [14]
Another source of smooth muscle disorders like ischemia–reperfusion, hypertension, and coronary artery disease arise when mutations to protein kinase C (PKC) result in excessive inhibition of MYLP, which counteracts the activity of MYLK by dephosphorylating myosin light chain. Because myosin light chain has no inherent phosphate cleaving property over active PKC prevents the dephosphorylation of myosin light protein leaving it in the activated conformation, causing an increase in smooth muscle contraction. [12]
Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the binding of Ca2+ is required for the activation of calmodulin. Once bound to Ca2+, calmodulin acts as part of a calcium signal transduction pathway by modifying its interactions with various target proteins such as kinases or phosphatases.
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations. It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit muscle, the whole bundle or sheet of smooth muscle cells contracts as a syncytium.
A myofibril is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofibril has a diameter of 1–2 micrometres. They are created during embryonic development in a process known as myogenesis.
A sarcomere is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells which are formed during embryonic myogenesis. Muscle fibers contain numerous tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as alternating dark and light bands. Sarcomeres are composed of long, fibrous proteins as filaments that slide past each other when a muscle contracts or relaxes. The costamere is a different component that connects the sarcomere to the sarcolemma.
Myosins are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.
Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding something heavy in the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.
Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.
CAMK, also written as CaMK or CCaMK, is an abbreviation for the Ca2+/calmodulin-dependent protein kinase class of enzymes. CAMKs are activated by increases in the concentration of intracellular calcium ions (Ca2+) and calmodulin. When activated, the enzymes transfer phosphates from ATP to defined serine or threonine residues in other proteins, so they are serine/threonine-specific protein kinases. Activated CAMK is involved in the phosphorylation of transcription factors and therefore, in the regulation of expression of responding genes. CAMK also works to regulate the cell life cycle (i.e. programmed cell death), rearrangement of the cell's cytoskeletal network, and mechanisms involved in the learning and memory of an organism.
Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the contractile proteins and titin is an elastic protein. The myofilaments act together in muscle contraction, and in order of size are a thick one of mostly myosin, a thin one of mostly actin, and a very thin one of mostly titin.
Telokin is an abundant protein found in smooth-muscle. It is identical to the C-terminus of myosin light-chain kinase. Telokin may play a role in the stabilization of unphosphorylated smooth-muscle myosin filaments. Because of its origin as the C-terminal end of smooth muscle myosin light chain kinase, it is called "telokin".
Calmodulin-binding proteins are, as their name implies, proteins which bind calmodulin. Calmodulin can bind to a variety of proteins through a two-step binding mechanism, namely "conformational and mutually induced fit", where typically two domains of calmodulin wrap around an emerging helical calmodulin binding domain from the target protein.
Caldesmon is a protein that in humans is encoded by the CALD1 gene.
Myosin light-chain phosphatase, also called myosin phosphatase (EC 3.1.3.53; systematic name [myosin-light-chain]-phosphate phosphohydrolase), is an enzyme (specifically a serine/threonine-specific protein phosphatase) that dephosphorylates the regulatory light chain of myosin II:
A myosin light chain is a light chain of myosin. Myosin light chains were discovered by Chinese biochemist Cao Tianqin when he was a graduate student at the University of Cambridge in England.
Calcium/calmodulin-dependent protein kinase type II gamma chain is an enzyme that in humans is encoded by the CAMK2G gene.
Myosin light chain kinase, smooth muscle also known as kinase-related protein (KRP) or telokin is an enzyme that in humans is encoded by the MYLK gene.
Myosin light chain kinase 3 also known as MYLK3, is an enzyme which in humans is encoded by the MYLK3 gene.
Myosin light chain kinase 2 also known as MYLK2 is an enzyme which in humans is encoded by the MYLK2 gene.
Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton.
Calponin 1 is a basic smooth muscle protein that in humans is encoded by the CNN1 gene.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.