{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:52:48Z","timestamp":1778658768796,"version":"3.51.4"},"reference-count":25,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,4,15]]},"abstract":"<jats:p>Besides functioning as the plasma transporter of retinol and thyroxine, TTR (transthyretin) is a protease, cleaving apoA-I (apolipoprotein A-I) after a phenylalanine residue. In the present study, we further investigated TTR substrate specificity. By using both P-diverse libraries and a library of phosphonate inhibitors, a TTR preference for a lysine residue in P1 was determined, suggesting that TTR might have a dual specificity and that, in addition to apoA-I, other TTR substrates might exist. Previous studies revealed that TTR is involved in the homoeostasis of the nervous system, as it participates in neuropeptide maturation and enhances nerve regeneration. We investigated whether TTR proteolytic activity is involved in these functions. Both wild-type TTR and TTRprot\u2212 (proteolytically inactive TTR) had a similar effect in the expression of peptidylglycine \u03b1-amidating mono-oxygenase, the rate-limiting enzyme in neuropeptide amidation, excluding the involvement of TTR proteolytic activity in neuropeptide maturation. However, TTR was able to cleave amidated NPY (neuropeptide Y), probably contributing to the increased NPY levels reported in TTR-knockout mice. To assess the involvement of TTR proteolytic activity in axonal regeneration, neurite outgrowth of cells cultivated with wild-type TTR or TTRprot\u2212, was measured. Cells grown with TTRprot\u2212 displayed decreased neurite length, thereby suggesting that TTR proteolytic activity is important for its function as a regeneration enhancer. By showing that TTR is able to cleave NPY and that its proteolytic activity affects axonal growth, the present study shows that TTR has natural substrates in the nervous system, establishing further its relevance in neurobiology.<\/jats:p>","DOI":"10.1042\/bj20082090","type":"journal-article","created":{"date-parts":[[2009,1,13]],"date-time":"2009-01-13T14:31:00Z","timestamp":1231857060000},"page":"467-474","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Substrate specificity of transthyretin: identification of natural substrates in the nervous system"],"prefix":"10.1042","volume":"419","author":[{"given":"M\u00e1rcia\u00a0A.","family":"Liz","sequence":"first","affiliation":[{"name":"Nerve Regeneration Group, Instituto de Biologia Molecular e Celular - IBMC, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal"}]},{"given":"Carolina\u00a0E.","family":"Fleming","sequence":"additional","affiliation":[{"name":"Nerve Regeneration Group, Instituto de Biologia Molecular e Celular - IBMC, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal"}]},{"given":"Ana\u00a0F.","family":"Nunes","sequence":"additional","affiliation":[{"name":"Nerve Regeneration Group, Instituto de Biologia Molecular e Celular - IBMC, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal"}]},{"given":"Maria\u00a0R.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Group, Instituto de Biologia Molecular e Celular - IBMC, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal"},{"name":"ICBAS, University of Porto, 4099-033 Porto, Portugal"}]},{"given":"Fernando\u00a0M.","family":"Mar","sequence":"additional","affiliation":[{"name":"Nerve Regeneration Group, Instituto de Biologia Molecular e Celular - IBMC, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal"}]},{"given":"Youngchool","family":"Choe","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, CA 94143, U.S.A."}]},{"given":"Charles\u00a0S.","family":"Craik","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, CA 94143, U.S.A."}]},{"given":"James\u00a0C.","family":"Powers","sequence":"additional","affiliation":[{"name":"School of Chemistry and Biochemistry, and the Petit Institute for Bioscience and Bioengineering, Georgia Institute of Technology, GA 30332, U.S.A."}]},{"given":"Matthew","family":"Bogyo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford School of Medicine, CA 94305, U.S.A."}]},{"given":"M\u00f3nica\u00a0M.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Nerve Regeneration Group, Instituto de Biologia Molecular e Celular - IBMC, Rua do Campo Alegre, 823, 4150-180 Porto, Portugal"}]}],"member":"288","published-online":{"date-parts":[[2009,3,27]]},"reference":[{"key":"2021112214394615100_B1","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1016\/S0021-9258(18)93118-2","article-title":"The interaction of thyroxine with human plasma prealbumin and with the prealbumin\u2013retinol-binding protein complex","volume":"244","author":"Raz","year":"1969","journal-title":"J. Biol. Chem."},{"key":"2021112214394615100_B2","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/S0022-2275(20)32074-5","article-title":"Transthyretin in high density lipoproteins: association with apolipoprotein A-I","volume":"41","author":"Sousa","year":"2000","journal-title":"J. Lipid Res."},{"key":"2021112214394615100_B3","doi-asserted-by":"crossref","first-page":"21431","DOI":"10.1074\/jbc.M402212200","article-title":"Transthyretin, a new cryptic protease","volume":"279","author":"Liz","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021112214394615100_B4","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1194\/jlr.M700158-JLR200","article-title":"ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity","volume":"48","author":"Liz","year":"2007","journal-title":"J. Lipid Res."},{"key":"2021112214394615100_B5","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1007\/s00018-005-4544-2","article-title":"Deciphering cryptic proteases","volume":"62","author":"Liz","year":"2005","journal-title":"Cell. Mol. Life Sci."},{"key":"2021112214394615100_B6","doi-asserted-by":"crossref","first-page":"8214","DOI":"10.1016\/S0021-9258(17)39583-2","article-title":"Rat transthyretin (prealbumin): molecular cloning, nucleotide sequence, and gene expression in liver and brain","volume":"260","author":"Dickson","year":"1985","journal-title":"J. Biol. Chem."},{"key":"2021112214394615100_B7","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1515\/CCLM.2002.210","article-title":"The evolution of transthyretin synthesis in the choroid plexus","volume":"40","author":"Schreiber","year":"2002","journal-title":"Clin. Chem. Lab. Med."},{"key":"2021112214394615100_B8","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/0305-0491(91)90035-C","article-title":"Transthyretin (prealbumin) gene expression in choroid plexus is strongly conserved during evolution of vertebrates","volume":"99","author":"Harms","year":"1991","journal-title":"Comp. Biochem. Physiol. Part B Biochem. Mol. Biol."},{"key":"2021112214394615100_B9","first-page":"R1359","article-title":"Evolution of marsupial and other vertebrate thyroxine-binding plasma proteins","volume":"266","author":"Richardson","year":"1994","journal-title":"Am. J. Physiol."},{"key":"2021112214394615100_B10","doi-asserted-by":"crossref","first-page":"13907","DOI":"10.1016\/S0021-9258(18)47880-5","article-title":"Thyroxine transport in choroid plexus","volume":"262","author":"Dickson","year":"1987","journal-title":"J. Biol. Chem."},{"key":"2021112214394615100_B11","first-page":"E485","article-title":"Transthyretin is not essential for thyroxine to reach the brain and other tissues in transthyretin-null mice","volume":"272","author":"Palha","year":"1997","journal-title":"Am. J. Physiol."},{"key":"2021112214394615100_B12","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.neulet.2007.05.040","article-title":"Cell division and apoptosis in the adult neural stem cell niche are differentially affected in transthyretin null mice","volume":"421","author":"Richardson","year":"2007","journal-title":"Neurosci. Lett."},{"key":"2021112214394615100_B13","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/humu.1132","article-title":"Transthyretin mutations in hyperthyroxinemia and amyloid diseases","volume":"17","author":"Saraiva","year":"2001","journal-title":"Hum. Mutat."},{"key":"2021112214394615100_B14","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1093\/brain\/75.3.408","article-title":"A peculiar form of peripheral neuropathy: familiar atypical generalized amyloidosis with special involvement of the peripheral nerves","volume":"75","author":"Andrade","year":"1952","journal-title":"Brain"},{"key":"2021112214394615100_B15","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1073\/pnas.90.6.2375","article-title":"Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone","volume":"90","author":"Episkopou","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112214394615100_B16","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1111\/j.1471-4159.2007.04828.x","article-title":"Transthyretin enhances nerve regeneration","volume":"103","author":"Fleming","year":"2007","journal-title":"J. Neurochem."},{"key":"2021112214394615100_B17","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1046\/j.1471-4159.2003.02309.x","article-title":"Transthyretin is involved in depression-like behaviour and exploratory activity","volume":"88","author":"Sousa","year":"2004","journal-title":"J. Neurochem."},{"key":"2021112214394615100_B18","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1096\/fj.05-4106fje","article-title":"Transthyretin knockouts are a new mouse model for increased neuropeptide Y","volume":"20","author":"Nunes","year":"2006","journal-title":"FASEB J."},{"key":"2021112214394615100_B19","doi-asserted-by":"crossref","first-page":"12824","DOI":"10.1074\/jbc.M513331200","article-title":"Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities","volume":"281","author":"Choe","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021112214394615100_B20","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nchembio.70","article-title":"Identification of proteases that regulate erythrocyte rupture by the malaria parasite Plasmodium falciparum","volume":"4","author":"Arastu-Kapur","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"2021112214394615100_B21","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1042\/BJ20040011","article-title":"Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative","volume":"381","author":"Almeida","year":"2004","journal-title":"Biochem. J."},{"key":"2021112214394615100_B22","doi-asserted-by":"crossref","first-page":"14420","DOI":"10.1074\/jbc.M010869200","article-title":"Internalization of transthyretin: evidence of a novel yet unidentified receptor-associated protein (RAP)-sensitive receptor","volume":"276","author":"Sousa","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112214394615100_B23","doi-asserted-by":"crossref","first-page":"5481","DOI":"10.1002\/j.1460-2075.1996.tb00933.x","article-title":"The 1.8 \u00c5 crystal structure of human cathepsin G in complex with Suc-Val-Pro-PheP-(OPh)2: a Janus-faced proteinase with two opposite specificities","volume":"15","author":"Hof","year":"1996","journal-title":"EMBO J."},{"key":"2021112214394615100_B24","first-page":"146","article-title":"Interaction of transthyretin with amyloid \u03b2-protein: binding and inhibition of amyloid formation","volume":"199","author":"Schwarzman","year":"1996","journal-title":"Ciba Found. Symp."},{"key":"2021112214394615100_B25","doi-asserted-by":"crossref","first-page":"e2899","DOI":"10.1371\/journal.pone.0002899","article-title":"Transthyretin protects against A-\u03b2 peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor","volume":"3","author":"Costa","year":"2008","journal-title":"PLoS ONE"}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/419\/2\/467\/659605\/bj4190467.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/419\/2\/467\/659605\/bj4190467.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T18:47:03Z","timestamp":1637606823000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/419\/2\/467\/45351\/Substrate-specificity-of-transthyretin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,3,27]]},"references-count":25,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2009,4,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20082090","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,3,27]]}}}