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It is unique among glycosaminoglycans as it is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus , and can be very large: human synovial HA averages about 7 million Da per molecule, or about 20, disaccharide monomers, [4] while other sources mention 3—4 million Da. As one of the chief components of the extracellular matrix , it contributes significantly to cell proliferation and migration , and also [ vague ] may be involved in the progression of some malignant tumors. Until the late s, hyaluronic acid was described as a " goo " molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix.

Robert Stern, Devising a pathway for hyaluronan catabolism: are we there yet? Hyaluronan is a negatively charged, high molecular weight glycosaminoglycan found predominantly in the extracellular matrix.

Textbook of Aging Skin pp Cite as. Hyaluronan is a major component of the extracellular matrix of skin and important in the metabolism of both epidermis and dermis. Hyaluronan is responsible for hydration, nutrient exchange, and protects against free radical damage via a multitude of signaling pathways.

Hyaluronic acid: A key molecule in skin aging

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Find more information on the Altmetric Attention Score and how the score is calculated. Mammalian hyaluronidases hydrolyze hyaluronan, a polysaccharide of diverse physiological roles found in all tissues and body fluids. In addition to its function in normal cellular hyaluronan turnover, human hyaluronidase-1 is implicated in cancer proliferation, angiogenesis, and inflammatory diseases; its expression is up-regulated in advanced stages of bladder cancer, whereas the expression of the alternative splice-variants is down-regulated.

The structure shows that the fold of this unique EGF-like domain is intact in four alternative splice-variants, whereas the catalytic domain is likely to be unfolded. Thus, these variants may function by competing with the full-length enzyme for the putative protein partner and regulating enzymatic activity in healthy cells.

The Advanced Photon Source is supported by the U. Corresponding author. Figure 1 Stereoscopic representation of the electron density map in the region of the active site together with the corresponding protein model. Figure 2 Structure of hHyal A Stereoscopic representation of a side view.

The catalytic and the HyalEGF-like domains are colored light blue and yellow, respectively. Disulfide bonds are shown in red. The color scheme is as in panel A. Labels of secondary structure units correspond to the labels in Figure 3.

The disulfide bonds are shown in red. Figure 3 Structure-based sequence alignment of human hyaluronidases. Invariant residues are shown in blue except for three key catalytic residues that are colored red. Cysteine residues are colored yellow.

The hHyal-1 N-glycosylated asparagines residues are colored turquoise. Residues exhibiting conservative replacements are blocked in blue. Pairs of cysteine residues that form disulfide bonds are indicated by stars with matching colors.

Secondary structure units are labeled as in Figure 2B. Figure 4 A Stereoscopic representation of the active site region of hHyal-1 gray ribbon superimposed on that of bvHyal yellow ribbon; A docked tetrasaccharide, inferred from the structure of bvHyal, is shown as a space filling model. Figure 5 Mapping of hHyal-1 splice variants numbered v1 to v5 on the intact structure. Deleted segments are highlighted in red.

Joseph L. Johnson for discussion about protein expression in Drosophila cells. View Author Information. Cite this: Biochemistry , 46 , 23 , — ACS AuthorChoice. Article Views Altmetric -. Citations Abstract High Resolution Image. HA is the major component of cartilage and serves as a joint lubricant. It controls water homeostasis in tissues and the extracellular matrix, which affects cell motility and the distribution and transport of plasma proteins.

The cellular role of HA and the HA-mediated signal transduction pathways depends on its size recently reviewed by Stern et al. Large HA polymers function in organizing the extracellular matrix and serve as lubricant and shock absorber.

In shock, septicemia, post surgery, blood loss, and burns, the level of circulating high molecular mass HA increases. These HA polymers are antiangiogenic, immunosuppressive, and anti-inflammatory. In contrast, HA fragments of intermediate sizes are involved in the body's alarm system. They stimulate angiogenesis and inflammatory reactions and facilitate cancer progression and invasion 4.

Short HA oligosaccharides are antiapoptotic and inducers of heat shock proteins. These genes exhibit different tissue distribution profiles. Human Hyal-1 and Hyal-2 are expressed in most tissues and are responsible for the catabolism of intracellular and extracellular HA, respectively 6, 7. With the exception of hHyal-1, the expressed hyaluronidases contain glycosylphosphatidylinositol-signal sequences and are membrane-bound upon maturation.

Human Hyal-3 is expressed in several tissues including the brain, yet its enzymatic activity and biological role are not well-defined. Human Hyal-4 was reported to be specific for chondroitin and chondroitin sulfate substrates 6. PH functions during fertilization. It degrades the HA-enriched cumulus of the oocyte during sperm penetration and then serves as the receptor for the sperm binding to the zona pellucida and induces HA-associated sperm signaling.

Human Hyal-1 is a lysosomal enzyme responsible for the hydrolysis of intracellular HA and is also detected in the plasma and in urine The enzyme is responsible for the production of angiogenic HA fragments. Inactivating mutations of hHyal-1 are linked to the human genetic disorder mucopolysaccharidosis IX, characterized by diminished stature, periarticular soft tissue masses, and absence of neurological and visceral involvement In humans, eight alternative splice transcripts of HYAL1 encode the full-length enzyme and five splice variants They lack enzymatic activity and are expressed at higher level in normal and in grade 1 bladder tumor tissues than in advanced cancer.

For example, hHyal-1 v1 expression is 2. Expression of splice variant v1 slows down bladder tumor growth, invasion, and angiogenesis by inducing the cellular apoptosis pathway The protein contains 10 cysteines, three predicted N-glycosylation sites, and an N-terminal endoplasmic reticulum signal sequence.

It cleaves HA substrates of all sizes into short chains, down to tetrasaccharides. No sequence homology has been reported in the scientific literature for the C-terminal domains of the mammalian hyaluronidases. In vitro biochemical studies of mammalian hyaluronidases have been hampered by the difficulties to produce the enzymes in soluble form. We have overcome this problem by producing recombinant hHyal-1 in Drosophila cells.

Here we report the crystal structure of the enzyme showing that it contains an EGF-like domain not seen previously, and examine the impact of alternative splicing on the enzyme structure and function. Materials and Methods. Protein was secreted from stably transfected Drosophila melanogaster Schneider 2 cells cotransfected with pCoPuro for selection with puromycin. Protein expression in the conditioned serum-free medium was detected by Western blot analysis with the monoclonal Penta-His Antibody Qiagen.

The cells were removed by centrifugation after 4 days, and the medium was applied directly onto a Chelating Sepharose Fast Flow column GE Health Sciences. The buffer was exchanged with 25 mM sodium acetate at pH 4. Protein concentration was determined using the BioRad Protein Assay in conjunction with spectrophotometric measurements calculated extinction coefficient of , M -1 cm Crystallization, Data Collection, and Structure Determination.

Crystals were obtained at room temperature by the hanging drop vapor diffusion method. The drops were equilibrated against the mother liquor reservoir. The rotation function Z -score was 4. The resulting electron density map revealed locations where side chains of the search model needed to be replaced by the correct side chains of hHyal Building of the HyalEGF-like domain and adjustments to the model were made on a graphics workstation using the program O De novo building of the C-terminal domain 83 amino acid residues was accomplished gradually as the model improved.

Overall Structure. Human Hyal-1 was readily crystallized at pH 4. Structure refinement at 2. All backbone torsion angles are within the allowed regions of the Ramachandran plot. High Resolution Image. In agreement with this finding, a search of the Protein Data Bank using DALI 31 identified the extracellular fragment of the heparin-binding EGF-like growth factor as the closest structural homologue of the hHyal-1 C-terminal domain 32 , albeit with a low Z -score of 2.

Sequence alignment Figure 3 shows that all other hyaluronidases contain the same structural domain; thus we term it a HyalEGF-like domain.

The close interaction between the two domains is also very different from the earlier prediction that proposed a flexible linker and lack of interactions between the two domains. Moreover, the modeling of the five human hyaluronidases C-terminal domains yielded a different fold in each case, whereas we expect that these domains adopt the HyalEGF-like fold because the amino acid sequences contain the characteristic disulfide bond pattern.

Protein Glycosylation. The mass difference of Da arises from post-translational N-linked glycosylation. The amino acid sequence of hHyal-1 contains three predicted N-glycosylation sites at Asn99, Asn, and Asn; thus the estimated average sugar mass is Da per site. This is in agreement with previously reported biantennary carbohydrates linked to proteins expressed in Drosophila cells 34, The electron density map of hHyal-1 indicated that all three potential glycosylation sites were modified.

The Asn modification was the largest seen and was modeled by the branched oligosaccharide: Asn99 N-glycosylation was less ordered and was modeled by GlcNAc 2. The oligosaccharide moieties of Asn99 and Asn form an intermolecular contact in the crystal. The most solvent exposed Asn was associated with weak electron density, which prevented modeling of sugar moieties.

Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory

Skin aging is a multifactorial process consisting of two distinct and independent mechanisms: intrinsic and extrinsic aging. Youthful skin retains its turgor, resilience and pliability, among others, due to its high content of water. Daily external injury, in addition to the normal process of aging, causes loss of moisture. The key molecule involved in skin moisture is hyaluronic acid HA that has unique capacity in retaining water. There are multiple sites for the control of HA synthesis, deposition, cell and protein association and degradation, reflecting the complexity of HA metabolism.

Importance of hyaluronan biosynthesis and degradation in cell differentiation and tumor formation. Abstract Text References Correspondence and Footnotes. Hyaluronan is an important connective tissue glycosaminoglycan. Elevated hyaluronan biosynthesis is a common feature during tissue remodeling under both physiological and pathological conditions. Through its interactions with hyaladherins, hyaluronan affects several cellular functions such as cell migration and differentiation.

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in HA metabolism, as well as developing bacterial fermentation Hyaluronan is widely diffused in nature: it is present in humans, biology and mechanisms of action are necessary to clarify all these madvirgin.org​Statistics//plastic-surgery-statistics-reportpdf (accessed.


Hyaluronan and the Process of Aging in Skin

These metrics are regularly updated to reflect usage leading up to the last few days. Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts. The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.

These metrics are regularly updated to reflect usage leading up to the last few days. Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts. The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.

Hyaluronan is a matrix polymer prominent in tissues undergoing rapid growth, development, and repair, in embryology and during malignant progression.

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4 Comments

Faust L. 10.05.2021 at 22:59

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Susan G. 11.05.2021 at 13:47

Metabolism and mechanisms of action of hyaluronan in human biology of hyaluronan are reviewed, focusing on human biological context.

Cuwazeby 12.05.2021 at 03:35

Hyaluronic acid also known as hyaluronan or hyaluronate is naturally found in many tissues and fluids, but more abundantly in articular cartilage and synovial fluid SF.

Cosette D. 13.05.2021 at 14:28

Double displacement reaction mechanism by class I Hyals in humans. The catalytic mechanism involves a series of intermediate reactions initiated by the.

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