Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin
Disruption of the survival motor neuron (SMN) gene leads to selective loss of spinal motor neurons, resulting in the fatal human neurodegenerative disorder spinal muscular atrophy (SMA). SMN has been shown to function in spliceosomal small nuclear ribonucleoprotein (snRNP) biogenesis and pre-mRNA sp...
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| Veröffentlicht in: | The Journal of biological chemistry 2001-10, Vol.276 (42), p.38645-38651 |
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| container_title | The Journal of biological chemistry |
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| creator | Jones, Kevin W. Gorzynski, Karen Hales, Chadwick M. Fischer, Utz Badbanchi, Farah Terns, Rebecca M. Terns, Michael P. |
| description | Disruption of the survival motor neuron (SMN) gene leads to selective loss of spinal motor neurons, resulting in the fatal human neurodegenerative disorder spinal muscular atrophy (SMA). SMN has been shown to function in spliceosomal small nuclear ribonucleoprotein (snRNP) biogenesis and pre-mRNA splicing. We have demonstrated that SMN also interacts with fibrillarin, a highly conserved nucleolar protein that is associated with all Box C/D small nucleolar RNAs and functions in processing and modification of rRNA. Fibrillarin and SMN co-immunoprecipitate from HeLa cell extracts indicating that the proteins exist as a complex in vivo. Furthermore, in vitro binding studies indicate that the interaction between SMN and fibrillarin is direct and salt-stable. We show that the glycine/arginine-rich domain of fibrillarin is necessary and sufficient for SMN binding and that the region of SMN encoded by exon 3, including the Tudor domain, mediates the binding of fibrillarin. Tudor domain missense mutations, including one found in an SMA patient, impair the interaction between SMN and fibrillarin (as well as the common snRNP protein SmB). Our results suggest a function for SMN in small nucleolar RNP biogenesis (akin to its known role as an snRNP assembly factor) and reveal a potential link between small nucleolar RNP biogenesis and SMA. |
| doi_str_mv | 10.1074/jbc.M106161200 |
| format | Article |
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SMN has been shown to function in spliceosomal small nuclear ribonucleoprotein (snRNP) biogenesis and pre-mRNA splicing. We have demonstrated that SMN also interacts with fibrillarin, a highly conserved nucleolar protein that is associated with all Box C/D small nucleolar RNAs and functions in processing and modification of rRNA. Fibrillarin and SMN co-immunoprecipitate from HeLa cell extracts indicating that the proteins exist as a complex in vivo. Furthermore, in vitro binding studies indicate that the interaction between SMN and fibrillarin is direct and salt-stable. We show that the glycine/arginine-rich domain of fibrillarin is necessary and sufficient for SMN binding and that the region of SMN encoded by exon 3, including the Tudor domain, mediates the binding of fibrillarin. Tudor domain missense mutations, including one found in an SMA patient, impair the interaction between SMN and fibrillarin (as well as the common snRNP protein SmB). Our results suggest a function for SMN in small nucleolar RNP biogenesis (akin to its known role as an snRNP assembly factor) and reveal a potential link between small nucleolar RNP biogenesis and SMA.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M106161200</identifier><identifier>PMID: 11509571</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Animals ; Arginine - chemistry ; Cell Nucleolus - metabolism ; Chromosomal Proteins, Non-Histone - chemistry ; Chromosomal Proteins, Non-Histone - genetics ; Chromosomal Proteins, Non-Histone - metabolism ; Cyclic AMP Response Element-Binding Protein ; DNA, Complementary - metabolism ; Exons ; fibrillarin ; Gene Library ; Glycine - chemistry ; HeLa Cells ; Humans ; Molecular Sequence Data ; Mutation, Missense ; Nerve Tissue Proteins - chemistry ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Precipitin Tests ; Protein Binding ; Protein Structure, Tertiary ; RNA-Binding Proteins ; SMN Complex Proteins ; SMN protein ; snoRNA ; snRNP proteins ; spinal muscular atrophy ; Two-Hybrid System Techniques ; Xenopus</subject><ispartof>The Journal of biological chemistry, 2001-10, Vol.276 (42), p.38645-38651</ispartof><rights>2001 © 2001 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c485t-ab956dd73569e6e16b5dd8d494273829dc48344d46d517112f82c1f05baca5433</citedby><cites>FETCH-LOGICAL-c485t-ab956dd73569e6e16b5dd8d494273829dc48344d46d517112f82c1f05baca5433</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11509571$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jones, Kevin W.</creatorcontrib><creatorcontrib>Gorzynski, Karen</creatorcontrib><creatorcontrib>Hales, Chadwick M.</creatorcontrib><creatorcontrib>Fischer, Utz</creatorcontrib><creatorcontrib>Badbanchi, Farah</creatorcontrib><creatorcontrib>Terns, Rebecca M.</creatorcontrib><creatorcontrib>Terns, Michael P.</creatorcontrib><title>Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Disruption of the survival motor neuron (SMN) gene leads to selective loss of spinal motor neurons, resulting in the fatal human neurodegenerative disorder spinal muscular atrophy (SMA). SMN has been shown to function in spliceosomal small nuclear ribonucleoprotein (snRNP) biogenesis and pre-mRNA splicing. We have demonstrated that SMN also interacts with fibrillarin, a highly conserved nucleolar protein that is associated with all Box C/D small nucleolar RNAs and functions in processing and modification of rRNA. Fibrillarin and SMN co-immunoprecipitate from HeLa cell extracts indicating that the proteins exist as a complex in vivo. Furthermore, in vitro binding studies indicate that the interaction between SMN and fibrillarin is direct and salt-stable. We show that the glycine/arginine-rich domain of fibrillarin is necessary and sufficient for SMN binding and that the region of SMN encoded by exon 3, including the Tudor domain, mediates the binding of fibrillarin. Tudor domain missense mutations, including one found in an SMA patient, impair the interaction between SMN and fibrillarin (as well as the common snRNP protein SmB). Our results suggest a function for SMN in small nucleolar RNP biogenesis (akin to its known role as an snRNP assembly factor) and reveal a potential link between small nucleolar RNP biogenesis and SMA.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Arginine - chemistry</subject><subject>Cell Nucleolus - metabolism</subject><subject>Chromosomal Proteins, Non-Histone - chemistry</subject><subject>Chromosomal Proteins, Non-Histone - genetics</subject><subject>Chromosomal Proteins, Non-Histone - metabolism</subject><subject>Cyclic AMP Response Element-Binding Protein</subject><subject>DNA, Complementary - metabolism</subject><subject>Exons</subject><subject>fibrillarin</subject><subject>Gene Library</subject><subject>Glycine - chemistry</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Molecular Sequence Data</subject><subject>Mutation, Missense</subject><subject>Nerve Tissue Proteins - chemistry</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Precipitin Tests</subject><subject>Protein Binding</subject><subject>Protein Structure, Tertiary</subject><subject>RNA-Binding Proteins</subject><subject>SMN Complex Proteins</subject><subject>SMN protein</subject><subject>snoRNA</subject><subject>snRNP proteins</subject><subject>spinal muscular atrophy</subject><subject>Two-Hybrid System Techniques</subject><subject>Xenopus</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkT1vFDEQhi0EIkegpUQuEN0eHq-9H-UpIRApdyACEp3ltWdZR3vrw_YSpeSf47AnUiGmmeZ5X43mIeQlsDWwWry96cx6C6yCCjhjj8gKWFMWpYRvj8mKMQ5Fy2VzQp7FeMPyiBaekhMAyVpZw4r8OncBTaKXU8KgTXJ-or6naUB6fXCTHul2jmYedaCbFPxhuKPnLqKOSD8Fn9BN9Hq7o7cuDUtor8eR7mYzor8Pfd5tCh2jN04ntH8zF64LbsyAm56TJ70eI7447lPy9eLdl7MPxdXH95dnm6vCiEamQnetrKytS1m1WCFUnbS2saIVvC4b3tqMlUJYUVkJNQDvG26gZ7LTRktRlqfkzdJ7CP7HjDGpvYsG8xET-jmqmkNby_y9_4HQABMVazO4XkATfIwBe3UIbq_DnQKm7u2obEc92MmBV8fmudujfcCPOjLwegEG9324zWZU57wZcK94XSnBVdlUQmasWTDM__rpMKhoHE4G7R-Zynr3rxN-A-cBqac</recordid><startdate>20011019</startdate><enddate>20011019</enddate><creator>Jones, Kevin W.</creator><creator>Gorzynski, Karen</creator><creator>Hales, Chadwick M.</creator><creator>Fischer, Utz</creator><creator>Badbanchi, Farah</creator><creator>Terns, Rebecca M.</creator><creator>Terns, Michael P.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20011019</creationdate><title>Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin</title><author>Jones, Kevin W. ; Gorzynski, Karen ; Hales, Chadwick M. ; Fischer, Utz ; Badbanchi, Farah ; Terns, Rebecca M. ; Terns, Michael P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c485t-ab956dd73569e6e16b5dd8d494273829dc48344d46d517112f82c1f05baca5433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Arginine - chemistry</topic><topic>Cell Nucleolus - metabolism</topic><topic>Chromosomal Proteins, Non-Histone - chemistry</topic><topic>Chromosomal Proteins, Non-Histone - genetics</topic><topic>Chromosomal Proteins, Non-Histone - metabolism</topic><topic>Cyclic AMP Response Element-Binding Protein</topic><topic>DNA, Complementary - metabolism</topic><topic>Exons</topic><topic>fibrillarin</topic><topic>Gene Library</topic><topic>Glycine - chemistry</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Molecular Sequence Data</topic><topic>Mutation, Missense</topic><topic>Nerve Tissue Proteins - chemistry</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Precipitin Tests</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>RNA-Binding Proteins</topic><topic>SMN Complex Proteins</topic><topic>SMN protein</topic><topic>snoRNA</topic><topic>snRNP proteins</topic><topic>spinal muscular atrophy</topic><topic>Two-Hybrid System Techniques</topic><topic>Xenopus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jones, Kevin W.</creatorcontrib><creatorcontrib>Gorzynski, Karen</creatorcontrib><creatorcontrib>Hales, Chadwick M.</creatorcontrib><creatorcontrib>Fischer, Utz</creatorcontrib><creatorcontrib>Badbanchi, Farah</creatorcontrib><creatorcontrib>Terns, Rebecca M.</creatorcontrib><creatorcontrib>Terns, Michael P.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jones, Kevin W.</au><au>Gorzynski, Karen</au><au>Hales, Chadwick M.</au><au>Fischer, Utz</au><au>Badbanchi, Farah</au><au>Terns, Rebecca M.</au><au>Terns, Michael P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2001-10-19</date><risdate>2001</risdate><volume>276</volume><issue>42</issue><spage>38645</spage><epage>38651</epage><pages>38645-38651</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Disruption of the survival motor neuron (SMN) gene leads to selective loss of spinal motor neurons, resulting in the fatal human neurodegenerative disorder spinal muscular atrophy (SMA). SMN has been shown to function in spliceosomal small nuclear ribonucleoprotein (snRNP) biogenesis and pre-mRNA splicing. We have demonstrated that SMN also interacts with fibrillarin, a highly conserved nucleolar protein that is associated with all Box C/D small nucleolar RNAs and functions in processing and modification of rRNA. Fibrillarin and SMN co-immunoprecipitate from HeLa cell extracts indicating that the proteins exist as a complex in vivo. Furthermore, in vitro binding studies indicate that the interaction between SMN and fibrillarin is direct and salt-stable. We show that the glycine/arginine-rich domain of fibrillarin is necessary and sufficient for SMN binding and that the region of SMN encoded by exon 3, including the Tudor domain, mediates the binding of fibrillarin. Tudor domain missense mutations, including one found in an SMA patient, impair the interaction between SMN and fibrillarin (as well as the common snRNP protein SmB). Our results suggest a function for SMN in small nucleolar RNP biogenesis (akin to its known role as an snRNP assembly factor) and reveal a potential link between small nucleolar RNP biogenesis and SMA.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>11509571</pmid><doi>10.1074/jbc.M106161200</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Animals Arginine - chemistry Cell Nucleolus - metabolism Chromosomal Proteins, Non-Histone - chemistry Chromosomal Proteins, Non-Histone - genetics Chromosomal Proteins, Non-Histone - metabolism Cyclic AMP Response Element-Binding Protein DNA, Complementary - metabolism Exons fibrillarin Gene Library Glycine - chemistry HeLa Cells Humans Molecular Sequence Data Mutation, Missense Nerve Tissue Proteins - chemistry Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Precipitin Tests Protein Binding Protein Structure, Tertiary RNA-Binding Proteins SMN Complex Proteins SMN protein snoRNA snRNP proteins spinal muscular atrophy Two-Hybrid System Techniques Xenopus |
| title | Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin |
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