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Structure and Function of Human Matrix Metalloproteinases

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Structure and Function of Human Matrix Metalloproteinases cells Review Review Structure and Function ofof HumanHuman Matrix MatrixMetalloproteinases Metalloproteinases 1,2 1,2, Helena Laronha 1,2 andand Jorge Jorge Caldeira Caldeira 1,2,* * 1 1 CentroCentro de de investigação investigação interdisci interdisciplinarplinar Egas Egas Moniz, Moniz, Instituto Instituto Univer Universitsitárioário Egas Egas Moniz, Moniz, Caparica 2829 Caparica, 2829, Portugal;Portugal; [email protected] [email protected] 2 UCIBIOUCIBIO and and LAQV LAQV Requimte Requimte Faculd Faculdadeade de de Ciências Ciências e eTecnologia, Tecnologia, Universidade Universidade Nova Nova de de Lisboa, Lisboa, 2829-516 Caparica,2829-516 Portugal Caparica, Portugal ** Correspondence:Correspondence: jcaldeira@egas [email protected];moniz.edu.pt; Tel. Tel.: +3519-1955-35-92+3519-1955-35-92 Received: 12 March 2020; Accepted: 21 April 2020; Published: date Received: 12 March 2020; Accepted: 21 April 2020; Published: 26 April 2020 Abstract: The extracellular matrix (ECM) is a macromolecules network, in which the most abundant Abstract: The extracellular matrix (ECM) is a macromolecules network, in which the most abundant molecule is collagen. This protein in triple helical conformation is highly resistant to proteinases molecule is collagen. This protein in triple helical conformation is highly resistant to proteinases degradation, the only enzymes capable of degrading the collagen are matrix metalloproteinases degradation, the only enzymes capable of degrading the collagen are matrix metalloproteinases (MMPs). This resistance and maintenance of collagen, and consequently of ECM, is involved in (MMPs). This resistance and maintenance of collagen, and consequently of ECM, is involved in several biological processes and it must be strictly regulated by endogenous inhibitors (TIMPs). The several biological processes and it must be strictly regulated by endogenous inhibitors (TIMPs). deregulation of MMPs activity leads to development of numerous diseases. This review shows The deregulation of MMPs activity leads to development of numerous diseases. This review shows MMPs complexity. MMPs complexity. Keywords: matrix metalloproteinases; TIMP; collagen Keywords: matrix metalloproteinases; TIMP; collagen 1. Extracellular Matrix—Collagen The extracellular matrix (ECM) is aa macromoleculesmacromolecules network,network, composedcomposed of collagen,collagen, enzymesenzymes and proteins (Figure1 1),), that that promote promote a a structural structural and and biochemical biochemical support. support. The ECMECM hashas manymany componentscomponents [[1]:1]: Fibers (collagen,(collagen, elastin, laminin, and and fibronectin), fibronectin), proteoglycans (syndecan-1 and aggrecan), glycoproteins (tenascin, vitronectin and entactin) and polysaccharides (hyaluronic(hyaluronic acid)acid) [[2],2], thatthat regulateregulate cellcell migration,migration, growth,growth, andand didifferentiationfferentiation [ 3[3].]. Figure 1. Schematic representation of the cell membrane. Cells 2020, 9, x; doi: FOR PEER REVIEW www.mdpi.com/journal/cells Cells 2020, 9, 1076; doi:10.3390/cells9051076 www.mdpi.com/journal/cells Cells 2020, 9, 1076 2 of 18 Cells 2020, 9, x FOR PEER REVIEW 2 of 19 The collagen is the most abundant protein in ECM which gives structural support for cells [1,3]. [1,3]. Depending of mineralization degree, the tissues can be divided in rigid (bones) or compliant compliant (sinews) (sinews) or have a gradientgradient betweenbetween these two statesstates (cartilage)(cartilage) [[4].4]. Collagen Collagen can can come come in in two main forms: fibrillarfibrillar (type I, II, III, V, andand XI)XI) andand non-fibrillar,non-fibrillar, thethe latterlatter includesincludes facit-fibrilfacit-fibril associatedassociated collagenscollagens with interrupted triple helix (type IX, XII, XIV, XIX,XIX, andand XXI);XXI); shortshort chain (type VIII and X); basement membrane (type IV); multiplexin (type XV and XVIII);XVIII); MACIT- membrane associatedassociated collagens with interrupted triple-helix (type XIII and XVII) and ot othershers types (Type VI, VII, and VIII). TheThe collagencollagen protein consistsconsists ofof threethree αα chains,chains, inin tripletriple helix,helix, wherewhere twotwo chainschains areare chemicallychemically similarsimilar ((αα11 and α2),), with approximate dimensions of 300 1.5 nm [3,5]. The triple helix is divided into five d-segments with approximate dimensions of 300 ×× 1.5 nm [3,5]. The triple helix is divided into five D-segments with D1–D4D1–D4 having a lengthlength ofof 6767 nmnm andand D5D5 equalequal toto 0.460.46 nmnm [[3,5].3,5]. TheThe highhigh glycineglycine contentcontent is important forfor collagen helix stabilization as it allows collagen fibers fibers to combine, facilitating hydrogen bridges and cross-link formationformation [[5].5]. The collagen synthesis involves several steps [5] [5] (Figure 22).). TheThe mRNAmRNA isis transcriptedtranscripted byby ribosome, forming pre-propeptide. pre-propeptide. The The following following thre threee stages stages occur occur in inthe the endoplasmic endoplasmic reticulum: reticulum: 1) (1)The The N-terminalN-terminal signal signal sequence sequence is isremoved; removed; 2) (2) hydroxylation hydroxylation of of lysine lysine and and proline proline by by prolylprolyl hydroxylase andand lysyllysyl hydroxylaseshydroxylases takestakes place,place, togethertogether withwith (3)3) glycosylation of lysine, forming the pro-collagen. This This structure structure is is a a triple triple helix helix chain, chain, but but with with the the unwound unwound terminals. terminals. The The removal removal of ofthese these terminals terminals occurs occurs in extracellular in extracellular medium, medium, by collagen by collagen peptidases, peptidases, forming forming tropocollagen. tropocollagen. The Themicrofibril microfibril collagen collagen is formed is formed by lysyl by lysyloxidase oxidase that packs that packstogether together five tropocollagen five tropocollagen chain [3], chain which [3], whichhave a have characteristic a characteristic image. image. At intervals At intervals of 67 of nm, 67 nm, one one zone zone has has the the roll roll of of all all tropocollagen tropocollagen and another zonezone has has one one less—“gap”. less—“gap”. The The fibril fibril collagen collagen is composed is composed of various of various microfibril microfibril collagen collagen group andgroup the and alternating the alternating overlap overlap and gap and regions gap regions create the create characteristic the characteristic “bright and“bright dark” andd -bandingdark” D- patternbanding [ 3pattern]. [3]. (a) (b) Figure 2. SynthesisSynthesis of of microfibril microfibril collagen. collagen. (a ()a In) In intracellular intracellular medium, medium, the the mRNA mRNA is transcripted is transcripted by byribosome, ribosome, forming forming the thepre-peptide, pre-peptide, which which is then is then processed processed in endoplasmic in endoplasmic reticulum, reticulum, forming forming pro- pro-collagen.collagen. (b) In (b )extracellular In extracellular medium, medium, the the pro-collagen pro-collagen is isprocessed processed by by collagen collagen peptidase, peptidase, forming tropocollagen. For microfibrilmicrofibril collagen formation,formation, thethe tropocollagentropocollagen isis processedprocessed byby lysillysil oxidase.oxidase. Its triple helix helix conformation conformation makes makes collagen collagen resi resistantstant to to many many proteases. proteases. The The enzymes enzymes able able to tocleave cleave this this structure structure are capthesin are capthesin K and K enzymes and enzymes with collagenolytic with collagenolytic activity activity(MMPs-1, (MMPs-1, -2, -8, -13, -2, - 14, and -18) [3,4]. The collagen type I, II and III have a specific cleavage sequence: (Gln/Leu)- Gly#(Ile/Leu)-(Ala/Pro), which is located at 3/4 of N-terminal and this is crucial for collagen Cells 2020, 9, 1076 3 of 18 Cells 2020, 9, x FOR PEER REVIEW 3 of 19 -8, -13, -14, and -18) [3,4]. The collagen type I, II and III have a specific cleavage sequence: (Gln/Leu)-Gly#(Ile/Leu)-(Ala/Pro), which is located at 3/4 of N-terminal and this is crucial for collagen degradation [6,7] (Figure 3). The denatured collagen is called gelatin, which can be further degraded degradation [6,7] (Figure3). The denatured collagen is called gelatin, which can be further degraded by gelatinases [4,6]. The collagen degradation is involved in many biological processes, such as by gelatinases [4,6]. The collagen degradation is involved in many biological processes, such as embryogenesis, morphogenesis, tissue remodulation, angiogenesis, and wound healing [4]. embryogenesis, morphogenesis, tissue remodulation, angiogenesis, and wound healing [4]. FigureFigure 3.3.Collagen Collagen degradation.degradation. TheThe enzymeenzyme withwith collagenolyticcollagenolytic activityactivity (collagenases)(collagenases) cleavescleaves thethe tripletriple helix helix at at two two fragments: fragments: 33/4/4 N N-terminal-terminal and and 1 1/4/4 C C-terminal.-terminal. EachEach chainchain ((αα11 andandα α2)2) hashas aa specificspecific cleavagecleavage sequencesequence (#(# representsrepresents the the cleavage cleavage site). site). TheThe ECMECM degradationdegradation isis alsoalso anan importantimportant processprocess inin development,development, morphogenesis,morphogenesis, tissuetissue repairrepair andand remodulationremodulation [[8],8], andand cancan aaffectffect the the cellular cellular
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