View source for ADAM10

{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox_gene}}
{{infobox enzyme
| Name       = ADAM10 endopeptidase
| EC_number  = 3.4.24.81
| CAS_number = 193099-09-1
| GO_code    =
| image      = 
| width      = 
| caption    =  
}}
'''A Disintegrin and metalloproteinase domain-containing protein 10''', also known as '''ADAM10''' or '''CDw156''' or '''CD156c''' is a [[protein]] that in humans is encoded by the ''ADAM10'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: ADAM10 ADAM metallopeptidase domain 10| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=102}}</ref>

== Function ==

Members of the [[a disintegrin and metalloproteinase|ADAM]] family are cell surface proteins with a unique structure, possessing both potential [[cell adhesion|adhesion]] and [[protease]] [[protein domain|domain]]s. Sheddase, a generic name for the ADAM metallopeptidase, functions primarily to cleave membrane proteins at the cellular surface. Once cleaved, the sheddases release soluble ectodomains with an altered location and function.<ref name="pmid15182168">{{cite journal | vauthors = Moss ML, Bartsch JW | title = Therapeutic benefits from targeting of ADAM family members | journal = Biochemistry | volume = 43 | issue = 23 | pages = 7227–7235 | date = June 2004 | pmid = 15182168 | doi = 10.1021/bi049677f }}</ref><ref name="pmid15596040">{{cite journal | vauthors = Nagano O, Saya H | title = Mechanism and biological significance of CD44 cleavage | journal = Cancer Science | volume = 95 | issue = 12 | pages = 930–935 | date = December 2004 | pmid = 15596040 | pmc = 11159127 | doi = 10.1111/j.1349-7006.2004.tb03179.x | s2cid = 9009213 | doi-access = free }}</ref><ref name="pmid15688065">{{cite journal | vauthors = Blobel CP | title = ADAMs: key components in EGFR signalling and development | journal = Nature Reviews. Molecular Cell Biology | volume = 6 | issue = 1 | pages = 32–43 | date = January 2005 | pmid = 15688065 | doi = 10.1038/nrm1548 | s2cid = 7011302 }}</ref>

Although a single sheddase may “shed” a variety of substances, multiple sheddases can cleave the same substrate resulting in different consequences. This gene encodes an ADAM family member that cleaves many proteins including TNF-alpha and E-cadherin.<ref name="entrez"/>

ADAM10 (EC#: 3.4.24.81) is a [[sheddase]], and has a broad specificity for peptide hydrolysis reactions.<ref name="Brenda Database">{{cite web | title = Entry of ADAM10 endopeptidase (EC-Number 3.4.24.81 )| url = http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.81}}</ref>

ADAM10 cleaves [[eph receptor|ephrin]], within the ephrin/eph complex, formed between two cell surfaces. When ephrin is freed from the opposing cell, the entire ephrin/eph complex is endocytosed. This shedding in trans had not been previously shown, but may well be involved in other shedding events.<ref name="pmid16239146">{{cite journal | vauthors = Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB | title = Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans | journal = Cell | volume = 123 | issue = 2 | pages = 291–304 | date = October 2005 | pmid = 16239146 | doi = 10.1016/j.cell.2005.08.014 | s2cid = 7962666 | doi-access = free }}</ref>

In [[neuron]]s, ADAM10 is the most important enzyme, with [[alpha secretase|α-secretase]] activity for [[proteolysis|proteolytic]] processing of the [[amyloid precursor protein]].<ref>{{cite journal | vauthors = Haass C, Kaether C, Thinakaran G, Sisodia S | title = Trafficking and proteolytic processing of APP | journal = Cold Spring Harbor Perspectives in Medicine | volume = 2 | issue = 5 | pages = a006270 | date = May 2012 | pmid = 22553493 | pmc = 3331683 | doi = 10.1101/cshperspect.a006270 }}</ref> ADAM10, along with [[ADAM17]], cleaves the ectodomain of the triggering receptor expressed on myeloid cells 2 ([[TREM2]]), to produce soluble TREM2 (sTREM2), which has been proposed as a CSF and sera biomarker of neurodegeneration.<ref>{{cite journal | vauthors = Yang J, Fu Z, Zhang X, Xiong M, Meng L, Zhang Z | title = TREM2 ectodomain and its soluble form in Alzheimer's disease | journal = Journal of Neuroinflammation | volume = 17 | issue = 1 | pages = 204 | date = July 2020 | pmid = 32635934 | pmc = 7341574 | doi = 10.1186/s12974-020-01878-2 | doi-access = free }}</ref>

ADAM10 belongs to subfamily A, the most ancestral subfamily of ADAM proteins, which is shared by all major groups of [[animal]]s, [[choanoflagellate]]s, [[fungi]], and [[green algae]] from the class [[Mamiellophyceae]].<ref name="ada">{{cite journal | vauthors = Souza JS, Lisboa AB, Santos TM, Andrade MV, Neves VB, Teles-Souza J, Jesus HN, Bezerra TG, Falcão VG, Oliveira RC, Del-Bem LE | title = The evolution of ADAM gene family in eukaryotes | journal = Genomics | volume = 112 | issue = 5 | pages = 3108–3116 | date = September 2020 | pmid = 32437852 | doi = 10.1016/j.ygeno.2020.05.010 | s2cid = 218832838 | doi-access = free }}</ref>

== Structure ==

Although no crystallographic x-ray diffraction analyses have been published that depict the entire structure of ADAM10, one domain has been studied using this technique.  The disintegrin and cysteine-rich domain (shown to the right) plays an essential role in regulation of protease activity in vivo.  Recent experimental evidence suggests that this region, which is distinct from the active site, may be responsible for substrate specificity of the enzyme.  It is proposed that this domain binds to particular regions of the enzyme's substrate, allowing peptide bond hydrolysis to occur in well defined locations on certain substrate proteins.<ref name="pmid12460986">{{cite journal | vauthors = Smith KM, Gaultier A, Cousin H, Alfandari D, White JM, DeSimone DW | title = The cysteine-rich domain regulates ADAM protease function in vivo | journal = The Journal of Cell Biology | volume = 159 | issue = 5 | pages = 893–902 | date = December 2002 | pmid = 12460986 | pmc = 2173380 | doi = 10.1083/jcb.200206023 }}</ref>

The proposed active site of ADAM10 has been identified by sequence analysis, and is identical to enzymes in the Snake Venom metalloprotein domain family.  The consensus sequence for catalytically active ADAM proteins is '''HE'''XG'''H'''NLGXX'''H'''D.  Structural analysis of ADAM17, which has the same active site sequence as ADAM10, suggests that the three histidines in this sequence bind a Zn<sup>2+</sup> atom, and that the glutamate is the [[catalytic residue]].<ref name="pmid7593158">{{cite journal | vauthors = Wolfsberg TG, Primakoff P, Myles DG, White JM | title = ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions | journal = The Journal of Cell Biology | volume = 131 | issue = 2 | pages = 275–278 | date = October 1995 | pmid = 7593158 | pmc = 2199973 | doi = 10.1083/jcb.131.2.275 }}</ref>

== Catalytic mechanism ==

Although the exact mechanism of ADAM10 has not been thoroughly investigated, its active site is homologous to those of well studied zinc-proteases such as carboxypeptidase A and thermolysin.  Therefore, it is proposed that ADAM10 utilizes a similar mechanism as these enzymes.
In zinc proteases, the key catalytic elements have been identified as a glutamate residue and a Zn<sup>2+</sup> ion coordinated to histidine residues.<ref name="pmid2197984">{{cite journal | vauthors = Lolis E, Petsko GA | title = Transition-state analogues in protein crystallography: probes of the structural source of enzyme catalysis | journal = Annual Review of Biochemistry | volume = 59 | pages = 597–630 | year = 1990 | pmid = 2197984 | doi = 10.1146/annurev.bi.59.070190.003121 }}</ref>

The proposed mechanism begins with deprotonation of a water molecule by glutamate.  The resultant hydroxide initiates a nucleophilic attack on a carbonyl carbon on the peptide backbone, producing a tetrahedral intermediate.  This step is facilitated by electron withdrawal from oxygen by Zn<sup>2+</sup> and by zinc's subsequent stabilization of the negative charge on the oxygen atom in the intermediate state.  As electrons move down from the oxygen atom to re-form the double bond, the tetrahedral intermediate collapses to products with protonation of -NH by the glutamate residue.<ref name="pmid2197984"/>
<!-- Deleted image removed: [[Image:Proposed ADAM10 mechanism.JPG|650px|border|thumb|center|Proposed Mechanism of ADAM10 Peptide Hydrolysis]] -->

== Clinical significance ==

=== Brain diseases ===

ADAM10 plays a key role in the modulation of the molecular mechanisms responsible for dendritic spine formation, maturation and stabilization and in the regulation of the molecular organization of the glutamatergic synapse. Consequently, an alteration of ADAM10 activity is strictly correlated to the onset of different types of synaptopathies, ranging from neurodevelopmental disorders, i.e. autism spectrum disorders, to neurodegenerative diseases, i.e. Alzheimer's Disease.<ref name="MarcelloBorroni2017">{{cite journal | vauthors = Marcello E, Borroni B, Pelucchi S, Gardoni F, Di Luca M | title = ADAM10 as a therapeutic target for brain diseases: from developmental disorders to Alzheimer's disease | journal = Expert Opinion on Therapeutic Targets | volume = 21 | issue = 11 | pages = 1017–1026 | date = November 2017 | pmid = 28960088 | doi = 10.1080/14728222.2017.1386176 | s2cid = 46800368 }}</ref>

=== Malaria ===

A number of different proteins on the surface of ''[[Plasmodium falciparum]]'' malaria parasites help the invaders bind to red blood cells. But once attached to host blood cells, the parasites need to shed the 'sticky' surface proteins that would otherwise interfere with entrance into the cell. The Sheddase enzyme, specifically called PfSUB2 in this example, is required for the parasites to invade cells; without it, the parasites die. The sheddase is stored in and released from cellular compartments near the tip of the parasite, according to the study. Once on the surface, the enzyme attaches to a motor that shuttles it from front to back, liberating the sticky surface proteins. With these proteins removed, the parasite gains entrance into a red blood cell. The entire invasion lasts about 30 seconds and without this ADAM metallopeptidase, malaria would be ineffective at invading the red blood cells.<ref name="Malaria">{{cite web|title='Sheddase' helps the malaria parasite invade red blood cells |url=http://malaria.wellcome.ac.uk/doc_WTD023958.html |url-status=dead |archive-url=https://web.archive.org/web/20080412043004/http://malaria.wellcome.ac.uk/doc_WTD023958.html |archive-date=2008-04-12 }}</ref>

=== Cancer ===
A 2020 study found that ADAM10 enhances the proliferation, migration, and invasion of [[osteosarcoma]] cells by modulating the [[E-cadherin]]/[[β-catenin]] signaling pathway, with [[miR-122|miR-122-5p]] identified as a regulatory upstream target of ADAM10, suggesting that the miR-122-5p/ADAM10 axis may represent a potential therapeutic target for osteosarcoma.<ref name="pmid32256208">{{cite journal |vauthors=Yuan Q, Yu H, Chen J, Song X, Sun L |title=ADAM10 promotes cell growth, migration, and invasion in osteosarcoma via regulating E-cadherin/β-catenin signaling pathway and is regulated by miR-122-5p |journal=Cancer Cell International |volume=20 |issue= |pages=99 |date=2020 |pmid=32256208 |pmc=7106760 |doi=10.1186/s12935-020-01174-2|doi-access=free }}</ref><ref name="pmid34157437">{{cite journal |vauthors=Das S, Amin SA, Jha T |title=Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies |journal=European Journal of Medicinal Chemistry |volume=223 |issue= |pages=113623 |date=November 2021 |pmid=34157437 |doi=10.1016/j.ejmech.2021.113623}}</ref>

====Breast cancer====
In combination with low doses of [[herceptin]], selective ADAM10 inhibitors decrease proliferation in [[HER2/neu|HER2]] over-expressing cell lines while inhibitors, that do not inhibit ADAM10, have no impact. These results are consistent with ADAM10 being a major determinant of HER2 shedding, the inhibition of which, may provide a novel therapeutic approach for treating breast cancer and a variety of other cancers with active HER2 signaling.<ref name="pmid16627989">{{cite journal | vauthors = Liu PC, Liu X, Li Y, Covington M, Wynn R, Huber R, Hillman M, Yang G, Ellis D, Marando C, Katiyar K, Bradley J, Abremski K, Stow M, Rupar M, Zhuo J, Li YL, Lin Q, Burns D, Xu M, Zhang C, Qian DQ, He C, Sharief V, Weng L, Agrios C, Shi E, Metcalf B, Newton R, Friedman S, Yao W, Scherle P, Hollis G, Burn TC | title = Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells | journal = Cancer Biology & Therapy | volume = 5 | issue = 6 | pages = 657–664 | date = June 2006 | pmid = 16627989 | doi = 10.4161/cbt.5.6.2708 | s2cid = 23463401 | doi-access = free }}</ref>

The presence of the product of this gene in neuronal synapses in conjunction with protein [[AP2 adaptor complex|AP2]] has been seen in increased amounts in the hippocampal neurons of [[Alzheimer's disease]] patients.<ref>{{cite journal | vauthors = Marcello E, Saraceno C, Musardo S, Vara H, de la Fuente AG, Pelucchi S, Di Marino D, Borroni B, Tramontano A, Pérez-Otaño I, Padovani A, Giustetto M, Gardoni F, Di Luca M | title = Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease | journal = The Journal of Clinical Investigation | volume = 123 | issue = 6 | pages = 2523–2538 | date = June 2013 | pmid = 23676497 | pmc = 3668814 | doi = 10.1172/JCI65401 }}</ref>

== See also ==
* [[Cluster of differentiation]]
* [[ADAM17|ADAM 17 Metallopeptidase]]
* [[ADAM Protein]]

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Wolfsberg TG, Primakoff P, Myles DG, White JM | title = ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions | journal = The Journal of Cell Biology | volume = 131 | issue = 2 | pages = 275–278 | date = October 1995 | pmid = 7593158 | pmc = 2199973 | doi = 10.1083/jcb.131.2.275 }}
* {{cite journal | vauthors = O'Bryan JP, Fridell YW, Koski R, Varnum B, Liu ET | title = The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage | journal = The Journal of Biological Chemistry | volume = 270 | issue = 2 | pages = 551–557 | date = January 1995 | pmid = 7822279 | doi = 10.1074/jbc.270.2.551 | s2cid = 46190313 | doi-access = free }}
* {{cite journal | vauthors = Howard L, Lu X, Mitchell S, Griffiths S, Glynn P | title = Molecular cloning of MADM: a catalytically active mammalian disintegrin-metalloprotease expressed in various cell types | journal = The Biochemical Journal | volume = 317 ( Pt 1) | issue = Pt 1 | pages = 45–50 | date = July 1996 | pmid = 8694785 | pmc = 1217484 | doi = 10.1042/bj3170045 }}
* {{cite journal | vauthors = McKie N, Edwards T, Dallas DJ, Houghton A, Stringer B, Graham R, Russell G, Croucher PI | title = Expression of members of a novel membrane linked metalloproteinase family (ADAM) in human articular chondrocytes | journal = Biochemical and Biophysical Research Communications | volume = 230 | issue = 2 | pages = 335–339 | date = January 1997 | pmid = 9016778 | doi = 10.1006/bbrc.1996.5957 }}
* {{cite journal | vauthors = Rosendahl MS, Ko SC, Long DL, Brewer MT, Rosenzweig B, Hedl E, Anderson L, Pyle SM, Moreland J, Meyers MA, Kohno T, Lyons D, Lichenstein HS | title = Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases | journal = The Journal of Biological Chemistry | volume = 272 | issue = 39 | pages = 24588–24593 | date = September 1997 | pmid = 9305925 | doi = 10.1074/jbc.272.39.24588 | s2cid = 21399815 | doi-access = free }}
* {{cite journal | vauthors = Yamazaki K, Mizui Y, Tanaka I | title = Radiation hybrid mapping of human ADAM10 gene to chromosome 15 | journal = Genomics | volume = 45 | issue = 2 | pages = 457–459 | date = October 1997 | pmid = 9344679 | doi = 10.1006/geno.1997.4910 }}
* {{cite journal | vauthors = Yamazaki K, Mizui Y, Sagane K, Tanaka I | title = Assignment of a disintegrin and metalloproteinase domain 10 (Adam10) gene to mouse chromosome 9 | journal = Genomics | volume = 46 | issue = 3 | pages = 528–529 | date = December 1997 | pmid = 9441766 | doi = 10.1006/geno.1997.5043 }}
* {{cite journal | vauthors = Yavari R, Adida C, Bray-Ward P, Brines M, Xu T | title = Human metalloprotease-disintegrin Kuzbanian regulates sympathoadrenal cell fate in development and neoplasia | journal = Human Molecular Genetics | volume = 7 | issue = 7 | pages = 1161–1167 | date = July 1998 | pmid = 9618175 | doi = 10.1093/hmg/7.7.1161 | doi-access = free }}
* {{cite journal | vauthors = Dallas DJ, Genever PG, Patton AJ, Millichip MI, McKie N, Skerry TM | title = Localization of ADAM10 and Notch receptors in bone | journal = Bone | volume = 25 | issue = 1 | pages = 9–15 | date = July 1999 | pmid = 10423016 | doi = 10.1016/S8756-3282(99)00099-X }}
* {{cite journal | vauthors = Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ | title = Shotgun sequencing of the human transcriptome with ORF expressed sequence tags | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 7 | pages = 3491–3496 | date = March 2000 | pmid = 10737800 | pmc = 16267 | doi = 10.1073/pnas.97.7.3491 | doi-access = free | bibcode = 2000PNAS...97.3491D }}
* {{cite journal | vauthors = Hattori M, Osterfield M, Flanagan JG | title = Regulated cleavage of a contact-mediated axon repellent | journal = Science | volume = 289 | issue = 5483 | pages = 1360–1365 | date = August 2000 | pmid = 10958785 | doi = 10.1126/science.289.5483.1360 | bibcode = 2000Sci...289.1360H | doi-access = free }}
* {{cite journal | vauthors = Vincent B, Paitel E, Saftig P, Frobert Y, Hartmann D, De Strooper B, Grassi J, Lopez-Perez E, Checler F | title = The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein | journal = The Journal of Biological Chemistry | volume = 276 | issue = 41 | pages = 37743–37746 | date = October 2001 | pmid = 11477090 | doi = 10.1074/jbc.M105677200 | doi-access = free }}
* {{cite journal | vauthors = Chubinskaya S, Mikhail R, Deutsch A, Tindal MH | title = ADAM-10 protein is present in human articular cartilage primarily in the membrane-bound form and is upregulated in osteoarthritis and in response to IL-1alpha in bovine nasal cartilage | journal = The Journal of Histochemistry and Cytochemistry | volume = 49 | issue = 9 | pages = 1165–1176 | date = September 2001 | pmid = 11511685 | doi = 10.1177/002215540104900910 | s2cid = 6879742 | doi-access = free }}
* {{cite journal | vauthors = Lemjabbar H, Basbaum C | title = Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells | journal = Nature Medicine | volume = 8 | issue = 1 | pages = 41–46 | date = January 2002 | pmid = 11786905 | doi = 10.1038/nm0102-41 | s2cid = 7135441 }}
* {{cite journal | vauthors = Healy EF, Romano P, Mejia M, Lindfors G | title = Acetylenic inhibitors of ADAM10 and ADAM17: in silico analysis of potency and selectivity | journal = Journal of Molecular Graphics & Modelling | volume = 29 | issue = 3 | pages = 436–442 | date = November 2010 | pmid = 20863729 | doi = 10.1016/j.jmgm.2010.08.006 }}
* {{cite journal | vauthors = Arndt M, Lendeckel U, Röcken C, Nepple K, Wolke C, Spiess A, Huth C, Ansorge S, Klein HU, Goette A | title = Altered expression of ADAMs (A Disintegrin And Metalloproteinase) in fibrillating human atria | journal = Circulation | volume = 105 | issue = 6 | pages = 720–725 | date = February 2002 | pmid = 11839628 | doi = 10.1161/hc0602.103639 | s2cid = 10279346 | doi-access = free }}
* {{cite journal | vauthors = Colciaghi F, Borroni B, Pastorino L, Marcello E, Zimmermann M, Cattabeni F, Padovani A, Di Luca M | title = [alpha]-Secretase ADAM10 as well as [alpha]APPs is reduced in platelets and CSF of Alzheimer disease patients | journal = Molecular Medicine | volume = 8 | issue = 2 | pages = 67–74 | date = February 2002 | pmid = 12080182 | pmc = 2039975 | doi = 10.1007/BF03402076 }}
* {{cite journal | vauthors = Lim R, Winteringham LN, Williams JH, McCulloch RK, Ingley E, Tiao JY, Lalonde JP, Tsai S, Tilbrook PA, Sun Y, Wu X, Morris SW, Klinken SP | title = MADM, a novel adaptor protein that mediates phosphorylation of the 14-3-3 binding site of myeloid leukemia factor 1 | journal = The Journal of Biological Chemistry | volume = 277 | issue = 43 | pages = 40997–41008 | date = October 2002 | pmid = 12176995 | doi = 10.1074/jbc.M206041200 | s2cid = 40077371 | doi-access = free }}
* {{cite journal | vauthors = Gatta LB, Albertini A, Ravid R, Finazzi D | title = Levels of beta-secretase BACE and alpha-secretase ADAM10 mRNAs in Alzheimer hippocampus | journal = NeuroReport | volume = 13 | issue = 16 | pages = 2031–2033 | date = November 2002 | pmid = 12438920 | doi = 10.1097/00001756-200211150-00008 }}
* {{cite journal | vauthors = Gutwein P, Mechtersheimer S, Riedle S, Stoeck A, Gast D, Joumaa S, Zentgraf H, Fogel M, Altevogt DP | title = ADAM10-mediated cleavage of L1 adhesion molecule at the cell surface and in released membrane vesicles | journal = FASEB Journal | volume = 17 | issue = 2 | pages = 292–294 | date = February 2003 | pmid = 12475894 | doi = 10.1096/fj.02-0430fje | s2cid = 21521110 | doi-access = free }}
{{refend}}

== External links ==
* {{UCSC genome browser|ADAM10}}
* {{UCSC gene details|ADAM10}}
* {{PDBe-KB2|O14672|Disintegrin and metalloproteinase domain-containing protein 10}}

{{NLM content}}
{{PDB Gallery|geneid=102}}
{{Clusters of differentiation}}
{{Metalloendopeptidases}}
{{Enzymes}}
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{{DEFAULTSORT:Adam10}}
[[Category:Proteases]]
[[Category:Clusters of differentiation]]
[[Category:Human proteins]]
[[Category:EC 3.4.24]]