Myosin light-chain kinase

myosin light-chain kinase 2, skeletal muscle
myosin light-chain kinase 2, skeletal muscle
	Crystal structure of the S. dubia centrin / human skeletal muscle myosin light-chain complex.
Identifiers
Symbol	MYLK2
NCBI gene	85366
HGNC	16243
OMIM	606566
RefSeq	NM_033118
UniProt	Q9H1R3
Other data
Locus	Chr. 20 q13.31
Structures
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Structures	Swiss-model
Domains	InterPro

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Structures	Swiss-model
Domains	InterPro

Myosin Light-Chain kinase, smooth muscle
Myosin Light-Chain kinase, smooth muscle
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
Structures
Search for
Structures	Swiss-model
Domains	InterPro

myosin light-chain kinase 3, cardiac

Identifiers

Symbol

Other data

Chr. 16 q11.2

Search for
Structures	Swiss-model
Domains	InterPro

Human Myosin Light-Chain Kinase

The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156.^[2]

Identifiers

Symbol

Search for
Structures	Swiss-model
Domains	InterPro

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]

General structural features

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]

Isoforms

Four different MYLK isoforms exist:^[6]

MYLK1 – smooth muscle
MYLK2 – skeletal
MYLK3 – cardiac
MYLK4 – novel

Function

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]

Upstream Regulators

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]

Image shows Myosin Light Chain Kinase protein allosterically activated by Calmodulin; Myosin Light Chain Kinase directly binds to Myosin II and phosphorylates it, causing a contraction. Rho Kinase A inhibits the activity of Myosin Light Chain Phosphatase. — Structural Diagram and Regulation of MYLK

Mutations and resulting diseases

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]

References

^ Radu, L.; Assairi, L.; Blouquit, Y.; Durand, D.; Miron, S.; Charbonnier, J.B.; Craescu, C.T. (2011). "RCSB Protein Data Bank - Structure Summary for 3KF9 - Crystal structure of the SdCen/skMLCK complex". Worldwide Protein Data Bank. doi:10.2210/pdb3kf9/pdb.
^ Muniz, J.R.C.; Mahajan, P.; Rellos, P.; Fedorov, O.; Shrestha, B.; Wang, J.; Elkins, J.M.; Daga, N.; Cocking, R.; Chaikuad, A.; Krojer, T.; Ugochukwu, E.; Yue, W.; von Delft, F.; Arrowsmith, C.H.; Edwards, A.M.; Weigelt, J.; Bountra, C.; Gileadi, O.; Knapp, S. (2010). "RCSB Protein Data Bank - Structure Summary for 2X4F - The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156". Worldwide Protein Data Bank. doi:10.2210/pdb2x4f/pdb.
^ Gao Y, Ye LH, Kishi H, Okagaki T, Samizo K, Nakamura A, Kohama K (June 2001). "Myosin light chain kinase as a multifunctional regulatory protein of smooth muscle contraction". IUBMB Life. 51 (6): 337–44. doi:10.1080/152165401753366087. PMID 11758800. S2CID 46180993.
^ Khapchaev AY, Shirinsky VP (December 2016). "Myosin Light Chain Kinase MYLK1: Anatomy, Interactions, Functions, and Regulation". Biochemistry. Biokhimiia. 81 (13): 1676–1697. doi:10.1134/S000629791613006X. PMID 28260490. S2CID 11424747.
^ Stull JT, Lin PJ, Krueger JK, Trewhella J, Zhi G (December 1998). "Myosin Light Chain Kinase: Functional Domains and Structural Motifs". Acta Physiologica. 164 (4): 471–482. doi:10.1111/j.1365-201X.1998.tb10699.x. PMID 9887970.
^ Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (December 2002). "The protein kinase complement of the human genome". Science. 298 (5600): 1912–34. Bibcode:2002Sci...298.1912M. doi:10.1126/science.1075762. PMID 12471243. S2CID 26554314.
^ Robinson A, Colbran R (2013). "Calcium/Calmodulin-Dependent Protein Kinases". In Lennarz W, Lane D (eds.). Encyclopedia of Biological Chemistry (2nd ed.). Elsevier inc. pp. 304–309. ISBN 978-0-12-378631-9.
^ Feher J (2017). "Smooth Muscle". Quantitative Human Physiology (2nd ed.). Elsevier inc. pp. 351–361. ISBN 978-0-12-800883-6.
^ Anjum I (January 2018). "Calcium sensitization mechanisms in detrusor smooth muscles". Journal of Basic and Clinical Physiology and Pharmacology. 29 (3): 227–235. doi:10.1515/jbcpp-2017-0071. PMID 29306925. S2CID 20486807.
^ Amano M, Nakayama M, Kaibuchi K (September 2010). "Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity". Cytoskeleton. 67 (9): 545–54. doi:10.1002/cm.20472. PMC 3038199. PMID 20803696.
^ Dudek SM, Garcia JG (October 2001). "Cytoskeletal regulation of pulmonary vascular permeability". Journal of Applied Physiology. 91 (4): 1487–500. doi:10.1152/jappl.2001.91.4.1487. PMID 11568129. S2CID 7042112.
^ ^a ^b Ringvold HC, Khalil RA (2017). "Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders". Vascular Pharmacology - Smooth Muscle. Advances in Pharmacology. Vol. 78. pp. 203–301. doi:10.1016/bs.apha.2016.06.002. ISBN 978-0-12-811485-8. PMC 5319769. PMID 28212798.
^ Szilágyi KL, Liu C, Zhang X, Wang T, Fortman JD, Zhang W, Garcia JG (February 2017). "Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome". Translational Research. 180: 12–21. doi:10.1016/j.trsl.2016.07.020. PMC 5253100. PMID 27543902.
^ Cunningham KE, Turner JR (July 2012). "Myosin Light Chain Kinase: Pulling the Strings of Epithelial Tight Junction Function". Annals of the New York Academy of Sciences. 1258 (1): 34–42. Bibcode:2012NYASA1258...34C. doi:10.1111/j.1749-6632.2012.06526.x. PMC 3384706. PMID 22731713.

External links

MYLK+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Myosin-Light-Chain+Kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

[3KF9-1] Radu, L.; Assairi, L.; Blouquit, Y.; Durand, D.; Miron, S.; Charbonnier, J.B.; Craescu, C.T. (2011). "RCSB Protein Data Bank - Structure Summary for 3KF9 - Crystal structure of the SdCen/skMLCK complex". Worldwide Protein Data Bank. doi:10.2210/pdb3kf9/pdb.

[2X4F-2] Muniz, J.R.C.; Mahajan, P.; Rellos, P.; Fedorov, O.; Shrestha, B.; Wang, J.; Elkins, J.M.; Daga, N.; Cocking, R.; Chaikuad, A.; Krojer, T.; Ugochukwu, E.; Yue, W.; von Delft, F.; Arrowsmith, C.H.; Edwards, A.M.; Weigelt, J.; Bountra, C.; Gileadi, O.; Knapp, S. (2010). "RCSB Protein Data Bank - Structure Summary for 2X4F - The Crystal Structure of the Human Myosin Light Chain Kinase Loc340156". Worldwide Protein Data Bank. doi:10.2210/pdb2x4f/pdb.

[pmid11758800-3] Gao Y, Ye LH, Kishi H, Okagaki T, Samizo K, Nakamura A, Kohama K (June 2001). "Myosin light chain kinase as a multifunctional regulatory protein of smooth muscle contraction". IUBMB Life. 51 (6): 337–44. doi:10.1080/152165401753366087. PMID 11758800. S2CID 46180993.

[pmid28260490-4] Khapchaev AY, Shirinsky VP (December 2016). "Myosin Light Chain Kinase MYLK1: Anatomy, Interactions, Functions, and Regulation". Biochemistry. Biokhimiia. 81 (13): 1676–1697. doi:10.1134/S000629791613006X. PMID 28260490. S2CID 11424747.

[5] Stull JT, Lin PJ, Krueger JK, Trewhella J, Zhi G (December 1998). "Myosin Light Chain Kinase: Functional Domains and Structural Motifs". Acta Physiologica. 164 (4): 471–482. doi:10.1111/j.1365-201X.1998.tb10699.x. PMID 9887970.

[pmid12471243-6] Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (December 2002). "The protein kinase complement of the human genome". Science. 298 (5600): 1912–34. Bibcode:2002Sci...298.1912M. doi:10.1126/science.1075762. PMID 12471243. S2CID 26554314.

[7] Robinson A, Colbran R (2013). "Calcium/Calmodulin-Dependent Protein Kinases". In Lennarz W, Lane D (eds.). Encyclopedia of Biological Chemistry (2nd ed.). Elsevier inc. pp. 304–309. ISBN 978-0-12-378631-9.

[8] Feher J (2017). "Smooth Muscle". Quantitative Human Physiology (2nd ed.). Elsevier inc. pp. 351–361. ISBN 978-0-12-800883-6.

[pmid29306925-9] Anjum I (January 2018). "Calcium sensitization mechanisms in detrusor smooth muscles". Journal of Basic and Clinical Physiology and Pharmacology. 29 (3): 227–235. doi:10.1515/jbcpp-2017-0071. PMID 29306925. S2CID 20486807.

[pmid20803696-10] Amano M, Nakayama M, Kaibuchi K (September 2010). "Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity". Cytoskeleton. 67 (9): 545–54. doi:10.1002/cm.20472. PMC 3038199. PMID 20803696.

[11] Dudek SM, Garcia JG (October 2001). "Cytoskeletal regulation of pulmonary vascular permeability". Journal of Applied Physiology. 91 (4): 1487–500. doi:10.1152/jappl.2001.91.4.1487. PMID 11568129. S2CID 7042112.

[pmid28212798-12] Ringvold HC, Khalil RA (2017). "Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders". Vascular Pharmacology - Smooth Muscle. Advances in Pharmacology. Vol. 78. pp. 203–301. doi:10.1016/bs.apha.2016.06.002. ISBN 978-0-12-811485-8. PMC 5319769. PMID 28212798.

[pmid27543902-13] Szilágyi KL, Liu C, Zhang X, Wang T, Fortman JD, Zhang W, Garcia JG (February 2017). "Epigenetic contribution of the myosin light chain kinase gene to the risk for acute respiratory distress syndrome". Translational Research. 180: 12–21. doi:10.1016/j.trsl.2016.07.020. PMC 5253100. PMID 27543902.

[14] Cunningham KE, Turner JR (July 2012). "Myosin Light Chain Kinase: Pulling the Strings of Epithelial Tight Junction Function". Annals of the New York Academy of Sciences. 1258 (1): 34–42. Bibcode:2012NYASA1258...34C. doi:10.1111/j.1749-6632.2012.06526.x. PMC 3384706. PMID 22731713.

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Myosin light-chain kinase

General structural features

Isoforms

Function

Upstream Regulators

Mutations and resulting diseases

See also

References

Further reading

External links

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