Human Molecular Genetics, 2001, Vol. 10, No. 24 2813-2820
© 2001 Oxford University Press
A new sequence motif linking lissencephaly, Treacher Collins and oral–facial–digital type 1 syndromes, microtubule dynamics and cell migration
MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Received August 10, 2001; Revised and Accepted September 21, 2001.
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ABSTRACT |
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A previously unidentified sequence motif has been identified in the products of genes mutated in Miller-Dieker lissencephaly, Treacher Collins, oral–facial–digital type 1 and contiguous syndrome ocular albinism with late onset sensorineural deafness syndromes. An additional homologous motif was detected in a gene product fused to the fibroblast growth factor receptor type 1 in patients with an atypical stem cell myeloproliferative disorder. In total, over 100 eukaryotic intracellular proteins are shown to possess a LIS1 homology (LisH) motif, including several katanin p60 subunits, muskelin, tonneau, LEUNIG, Nopp140, aimless and numerous WD repeat-containing ß-propeller proteins. It is suggested that LisH motifs contribute to the regulation of microtubule dynamics, either by mediating dimerization, or else by binding cytoplasmic dynein heavy chain or microtubules directly. The predicted secondary structure of LisH motifs, and their occurrence in homologues of Gß ß-propeller subunits, suggests that they are analogues of G
subunits, and might associate with the periphery of ß-propeller domains. The finding of LisH motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins. Uncharacterized LisH motif-containing proteins represent candidates for other diseases associated with aberrant microtubule dynamics and defects of cell migration, nucleokinesis or chromosome segregation. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Children with mutations in the LIS1 gene suffer from Miller-Dieker lissencephaly, a brain malformation that results in severe retardation, epilepsy and an early death. Patients exhibit a smooth cerebral surface that arises from neuronal migration defects (1,2). Understanding the molecular functions of the LIS1 protein has profited greatly from the identification of LIS1 orthologues in eukaryotic model organisms, including the fly Drosophila melanogaster and the filamentous fungus Aspergillus nidulans. In particular, investigations, of NudF the LIS1 orthologue in A.nidulans, have demonstrated its involvement in nuclear migration (3).
Recent studies have highlighted a role for LIS1 in the regulation of microtubule-association kinetics. Mammalian LIS1 was shown to associate with cytoplasmic dynein heavy chain (CDHC), an ATPase and microtubule motor (4,5). CDHC plays a central role in the microtubule-based transport of organelles and cytoskeletal components. This is particularly important for neurons due to their large size and polarity which is determined by the position of dendrites and axons. The characteristic form of these two processes is largely determined by the composition of microtubules within them. The growth of axons occurs by the addition, to the growing plus end, of small microtubule fragments that are released from the centrosome by katanin (6–8) and transported to the cell periphery by the CDHC-containing dynein complex and kinesin motor protein (9).
Mammalian LIS1 is proposed to up-regulate CDHC-mediated translocation of microtubule segments (4,5) and Drosophila LIS1 appears to regulate the integrity of the microtubule cytoskeleton (10). Further work has emphasized the LIS1-mediated regulation of the cellular localization of CDHC via its direct interaction with homologues of NudE, a second A.nidulans nuclear migration gene (5,11). NudE and LIS1 homologues were found to co-localize at centrosomes (5,11,12). These are specialized organelles that are responsible for microtubule nucleation and orientation and duplicate once every cell cycle (13).
The LIS1 sequence contains seven WD repeats. These are short repeats that associate in a closed ß-propeller domain similar to that seen in the ß-subunit of heterotrimeric G-proteins (14). In the standard model of G-protein signalling, the Gß and G subunits are tightly associated and bind G
GDP. Replacement of GDP by GTP in the G active site causes release of the Gß heterodimer, which is the major determinant of downstream signalling. The Gß heterotrimer is reformed only upon turnover of GTP to GDP. WD repeat-containing proteins can be divided into two classes (15): those that only contain WD repeats (such as Gß subunits) and those that also possess an N-terminal extension; LIS1 falls into the latter class.
Missense mutations of LIS1 have been demonstrated in lissencephaly patients that result in amino acid substitutions within two of its WD repeats, as well as in its N-terminal region (F31S) (16). The latter substitution lies close to a coiled coil structure between amino acids 44 and 78 (16). A LIS1 in vitro translation product lacking the first 65 amino acids appears to possess reduced microtubule-binding affinity (17). Thus, the N-terminus of LIS1 might bind microtubules directly, or else indirectly via an association with cytoplasmic dynein (4,18).
Invertebrate and mammalian LIS1, and A.nidulans NudF, exhibit strong sequence similarity not only within their WD repeat-containing ß-propeller region, but also in their N-terminal extensions. However, their regions outside of the ß-propeller region had not previously been demonstrated to be homologous to any other proteins. Here, we show that many WD repeat-containing, and other, proteins contain a LIS1-like conserved -helical motif that is likely to possess a conserved protein-binding function. The presence of this motif in the products of other disease genes, suggests links between the molecular and cellular deficiencies in lissencephaly, Treacher Collins syndrome (TCS) and oral–facial–digital type 1 (OFD1) syndrome.
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RESULTS |
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Searches of protein databases for sequences homologous to the N-terminal region of LIS1 initially revealed no significant similarities to other proteins. However, subtle, although insignificant, sequence similarities were observed between Caenorhabditis elegans LIS1 and two apparent repeats in an Arabidopsis thaliana gene (At2g25420). Further investigation of the plant gene product showed that it not only contains two novel repeats (P = 1.78 x 10–3) as assessed using Prospero (19) in its N-terminal region but also, in common with LIS1, multiple tandem WD repeats in its C-terminal regions. At2g25420 appears to be a plant homologue of C.elegans smu-1, a nuclear protein that regulates alternative splicing of unc-52 mRNA (20).
In order to investigate whether the novel repeats in At2g25420 are homologous to the N-terminal region of LIS1 homologues, the two repeats were aligned with the N-terminus of C.elegans LIS1 using MACAW (21); this resulted in an alignment score (P = 3.3 x 10–6) that is suggestive of homology. More definitive evidence that LIS1 homologues contain a motif that is present in other proteins required development of a three-step protein sequence database searching protocol (Fig. 1). Different iterative database search methods were used for each of the three steps: (i) MoST (22), (ii) HMMer (23) and (iii) PSI–BLAST (24).
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The protocol exploits the complementarity of the three database search methods: MoST detects similarities in ungapped alignment blocks, HMMer2 detects similarities in global gapped alignments and PSI–BLAST detects similarities in local gapped alignments. Use of PSI–BLAST alone was found to be unable to detect the majority of these homologues indicating that it is not the best method available for detecting short and un-gapped sequence motifs.
Starting with an ungapped alignment of eight sequences, each homologous to the tandem repeats in A.thaliana At2g25420, and cycling through the three-step search protocol three times, 114 non-identical candidate homologues’ sequences were detected before convergence (Table 1; Figs 2 and 3). At this stage we considered whether the set of candidate homologues might include evolutionary-unrelated, false positive, sequences. However, examination of the phyletic distribution of the 114 candidates revealed that all originate from eukaryotic organisms rather than from prokaryotes which represent a substantial fraction of the databases searched. Additionally, 45 of these 114 proteins contain WD repeats which are found in only 0.3% of all known proteins. Finally, the functions of many of the candidate LisH motif-containing proteins are associated with microtubule dynamics (see below). Each of these observations would not be expected if a significant fraction of the 114 candidate homologues were to have been selected at random from known sequences. Consequently, it is likely that most, if not all, the 114 contain homologous sequences and few, if any, are false positive homologues.
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represent those used for the initial MoST database search. Predicted secondary structures (25) are shown beneath the alignment. GeneInfo sequence identifiers and amino acid limits are shown to the right of the alignment. Abbreviations: At, A.thaliana; Ce, C.elegans; Dd, Dictyostelium discoideum; Dm, D.melanogaster; EMP, erythroblast macrophage attacher; En, Emericella nidulans; Flo8p, Flocculation protein 8; Fop, FGFR1 oncogene partner; Hs, H.sapiens; Lm, Leishmania major; Mm, Mus musculus; Nopp140, 140 kDa nucleolar phosphoprotein; RanBP, Ran-binding protein; Rn, Rattus norvegicus; Sc, Saccharomyces cerevisiae; Sif2p, Sir4p-interacting factor 2; Sp, S.pombe; VprBP, Vpr-binding protein; Xl, Xenopus laevis.
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The secondary structure of these homologues (Fig. 2) is predicted (25) to be two
-helices. Domains, defined as compact structural units with hydrophobic interiors, usually contain greater numbers of secondary structures. Consequently, these bi-helical homologues are likely to represent smaller structural entities, known as ‘motifs’; homologues of the LIS1 N-terminal region shall thenceforth be referred to as LisH motifs (LIS1-homologous motifs). The first cycle of database searches revealed five LisH motif-containing proteins that are associated with human disease. Human LIS1 was found in the fourth iteration of the MoST search step (E = 3.9 x 10–3). At the same iteration the transducin ß-like 1 gene product (TBL1) that is deleted in patients with contiguous syndrome ocular albinism with late onset sensorineural deafness (OASD) (26) was also detected (E = 7.9 x 10–6). Three iterations later in the same MoST search the Cxorf5 gene product, that is mutated in X-linked OFD1 (27) was detected (E = 1.1 x 10–2). The first HMMer2-based search identified a LisH motif (E = 3.3 x 10–3) in the product of a gene that is fused with the fibroblast growth factor receptor type 1 (FGFR1) in a stem cell myeloproliferative disorder (28). Finally, the MoST search in cycle 2 identified treacle, the product of the gene mutated in TCS (29), as a LisH motif-containing protein (iteration 2; E = 6.8 x 10–3).
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DISCUSSION |
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LisH motifs and disorders of cell migration
Three LisH motif-containing proteins, LIS1, treacle and Cxorf5, are associated with diseases characterized by defective cell migration. This suggests that their LisH motifs possess similar roles in comparable cellular processes that are defective in these disorders.
Mutations of LIS1 are associated with lissencephaly, which is a consequence of aberrant neuronal migration. In particular, a patient with low severity lissencephaly possesses a mutation (F31S) within its LisH motif; similarly, mice heterozygous for a LIS1 mutation, that removed its LisH motif and coiled coil regions (amino acids 1–63 inclusive), show aberrant morphology of the developing cortex consistent with an impairment of neuron migration (30).
Mutations in the gene coding for treacle results in TCS, an autosomal dominant disorder characterized by craniofacial abnormalities and hearing loss (29). This disorder also has been attributed to incorrect cell migration, namely neural crest cells from the first and second branchial arches during embryonic development (31). The tripartite structure of the treacle sequence, a N-terminal LisH motif, a central unit of repeating acidic and basic residues, and a C-terminal nuclear localization signal region, is similar to that of another nucleolar phosphoprotein Nopp140 (32) (Fig. 2), but this is the first occasion on which homology between the two proteins has been established.
Mutation of the Cxorf5 gene product, another LisH motif-containing protein, results in the X-linked disease OFD1 (27). OFD has been associated with a spectrum of CNS malformations including intracerebral cysts, porencephaly, absence of the corpus callosum and misrouting and disarrangement of the nerve fibres of the medulla (33–35). This suggests that the neuronal component of OFD syndrome is due to aberrant neuronal cell migration.
LisH motifs and other diseases
LisH motifs were found in an additional two human disease gene products that are not obviously associated with defects in cell migration.
Deletion of the LisH motif-containing protein TBL1, which contains six WD repeats, is associated with contiguous syndrome OASD (26). Whereas deafness associated with TCS is likely to be due to the malformation of the facial structures including the outer and middle ear, hearing loss in OASD is associated with the malformation of the auditory nerve. Mutation of Ebi, a Drosophila homologue of TBL1, in its LisH motif (Fig. 2), is associated with defects in neuronal differentiation (36).
The LisH motif of the FGFR1 oncogene partner (FOP) has been found to be fused to the catalytic domain of FGFR1 in patients with an atypical stem cell myeloproliferative disorder (28). In these cases, the FOP LisH motif might be involved in anomalous targeting of the protein tyrosine kinase to cytosolic, rather than the more normal juxtamembranous, structures within the cell.
LisH motif functions: dimerization, dynein, microtubules and ß-propellers?
Consideration of available experimental data on LisH motif-containing proteins (Table 1; Fig. 3) and comparisons with analogous molecular processes suggests four potential protein-binding functions for LisH motifs: self-association or binding to microtubules, ATPases or ß-propellers.
The N-terminal region of LIS1 (amino acids 1–95) mediates its homodimerization and contains both a LisH motif and a coiled coil region (30). Thus, either one, or both, of these two regions might mediate homodimerization. Of the two regions, the coiled coil structure is the more likely to homodimerize, since this is an established function of coiled coils, such as those in keratins and leucine zippers. Nevertheless, the possibility remains that LisH motifs might possess homodimerization properties.
LisH motifs might also be microtubule-binding structures. LIS1 and plant tonneau proteins are known to co-localize with microtubules (37,38) and the centrosomal protein RanBPM binds -tubulin in the yeast two-hybrid system (39). Nopp140 has been shown, by immunogold labelling, to shuttle proteins between the nucleolus and the cytoplasm on ‘cytoskeletal tracks’ (40) which might represent microtubules.
Three LisH motif-containing proteins, from mouse, Leishmania and Drosophila, are homologues of p60 katanin subunits. Katanin is a microtubule-stimulated ATPase that disassembles microtubules into tubulin dimers by disrupting the microtubule lattice. Strongylocentrotus purpuratus (sea urchin) katanin is a heterodimer of p60, that contains a C-terminal AAA ATPase involved in severing microtubules and an N-terminal microtubule-binding domain (41) and p80, containing six WD repeats. Although a LisH motif could not be detected with significance in the sea urchin p60 katanin subunit, subtle similarities to identified LisH motif sequences exist in the p60 N-terminal region, which suggests that some p60 katanin subunits might contain LisH motifs with sequences have diverged beyond recognition. If sea urchin p60 contains this N-terminal LisH motif, it is within the region thought to bind microtubules (41).
Other possible binding partners of LisH motifs are the AAA family of ATPase domains (42), which include domains in the CDHC and p80 katanin. LIS1 binds CDHC, and a LIS1 variant lacking its LisH motif and coiled coil region (amino acids 1–112) shows greatly reduced CDHC-binding capability (5). This interaction appears to involve the enzymatically active AAA ATPase domain in CDHC.
A G-like model for the LisH motif and microtubule dynamics
Of 114 LisH motif-containing proteins detected, 45 also contain WD repeats that are likely to adopt a ß-propeller structure (14). The unexpectedly large fraction of proteins with both a LisH motif and a ß-propeller domain suggests that their molecular functions might be tightly coupled or indeed that these structures might physically associate.
Analogies can be made between katanin and CDHC·LIS1 heterodimers, and G protein ß trimers since they all contain both a nucleotide triphosphatase (ATPase or GTPase) and a ß-propeller, WD repeat-containing, domain. The bi-helical LisH motif is reminiscent of, although not obviously homologous to, the G subunit in terms of its secondary structure content (43). Just as G subunits tightly associate with Gß subunits in G proteins, LisH motifs might also bind WD repeat-containing ß-propeller domains. This would occur either intra- or inter-molecularly since LisH motifs co-occur with WD repeats in the same protein (e.g. LIS1), and also in different proteins within the same complex (e.g. katanin). The analogy between LisH motifs and G subunit is made further relevant to microtubule structures since a microtubule-dependent ATPase, Drosophila kinesin Klp54D, contains a C-terminal G-like (GGL) domain (43).
This proposal that LisH motifs bind ß-propellers in a G·Gß-like manner is consistent with the findings that the LIS1 LisH motif-containing N-terminal region mediates its homodimerization (30) but only if the LisH motif were to bind its WD repeat-containing region in the trans orientation. It might also account for the abundance of WD repeat-containing proteins [including Cdc20p (44), LIS1, dynein intermediate chains (45), katanin p80 and EMAP (46)] known to be associated with microtubule function.
As microtubules perform important roles in vesicular transport, cellular organization and chromosome organization it is perhaps not surprising that LisH motifs have been found in five gene products that are associated with human disease. Indeed, the remaining LisH motif-containing proteins represent good candidates for other diseases associated with aberrant microtubule dynamics and defects of cell migration, nucleokinesis or chromosome segregation.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Coiled coils were predicted using COILS (47), as implemented at EMBnet (http://www.ch.embnet.org/software/COILS_form.html), and a window of 21 amino acids. Detection of previously known domains and repeats in protein sequences was achieved using SMART (48) (http://smart.embl-heidelberg.de). Detection of significantly similar protein repeats and estimation of their significance used Prospero (19). Secondary structure predictions were provided by PHD (25) (http://dodo.cpmc.columbia.edu/predictprotein/).
Comparison of A.thaliana At2g25420 and C.elegans LIS1 sequences used the ungapped alignment (segment pair overlap) search method of MACAW (21) and a searchspace equal to 1.32 x 108, the square of the number of amino acids in At2g25240 multiplied by the number of amino acids in C.elegans LIS1.
Protein sequence similarity searches employed two databases: nrdb90 (49) (http://www.ebi.ac.uk/~holm/nrdb90/) for which no two sequences are >90% identical, and the non-redundant (nr) database curated at the National Center for Biotechnology Information (ftp://ftp.ncbi.nlm.nih.gov/blast/db/nr), for which no two sequences are 100% identical. Each of the three database searching methods required the use of a different E-value inclusion threshold. The E-value of an alignment scoring x, is the number of sequences expected in this database search to be aligned with score x, or higher, by chance alone. In each of these methods those sequences with E-values lower than the E-value threshold are included in the profile or hidden Markov model (HMM) used in the subsequent iteration.
MoST searches (22) used nrdb90, an upper threshold of 80% for pairwise identities, and an E-value inclusion threshold of 1 x 10–2. This represents a conservative choice for this threshold (5 x 10–2 is more normally applied), but is more appropriate for ungapped alignments representing -helical structures. HMMer2 searches of nrdb90 employed HMMs calculated from multiple alignments and calibrated using the HMMer2 package and default parameters (23). An E-value inclusion threshold of 10–1 was applied. Lastly, homologous sequences that were detected within five search rounds using PSI–BLAST searches (24) and an E-value inclusion threshold of 2 x 10–3 were collated and their homologous regions detected by comparison with a HMM. Manipulation of sequences for PSI–BLAST searches was assisted by local implementation of SEALS scripts (50).
MoST, HMMer2 and PSI–BLAST approaches were applied in successive steps for three complete cycles (Fig. 1). The initial MoST database search used an ungapped alignment block containing the two At2g25420 repeats, together with single motifs from eukaryotic proteins (A.thaliana F7H2.9, C.elegans SMU-1, D.melanogaster CG7611, Homo sapiens FLJ10805 and KIAA0893 and Schizosaccharomyces pombe SPAC343.04c) that are detectable as At2g25420 homologues using PSI–BLAST and an E-value inclusion threshold of 2 x 10–3. The sequences of homologues identified by this MoST database search were multiply aligned and a HMM constructed. Candidate homologues that were detected using HMMer2 were added to the alignment and a further HMM was constructed that was compared once more with current databases. The resulting set of candidate homologues was then subjected to PSI–BLAST analysis. For these searches, the sequence of each candidate homologue was extended N- and C-terminally by 50 amino acids and then compared with the nr sequence database. A multiple alignment of all putative homologues that were detected using this three-step procedure was then prepared and used as the basis for second, and then third, cycles of database searches.
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ACKNOWLEDGEMENTS |
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We would like to thank Dr Leo Goodstadt for providing one of the Figures.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 1865 272175; Fax: +44 1865 282651; Email: chris.ponting@anat.ox.ac.uk
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