Structural analysis of tumor-related single amino acid mutations in human MxA protein
© Hu et al. 2015
Received: 3 June 2015
Accepted: 13 September 2015
Published: 28 September 2015
Human myxovirus resistant protein A (MxA), encoded by the myxovirus resistance 1 (Mx1) gene, is an interferon (IFN)-triggered dynamin-like multi-domain GTPase involved in innate immune responses against viral infections. Recent studies suggest that MxA is associated with several human cancers and may be a tumor suppressor and a promising biomarker for IFN therapy. Mx1 gene mutations in the coding region for MxA have been discovered in many types of cancer, suggesting potential biological associations between mutations in MxA protein and corresponding cancers. In this study, we performed a systematic analysis based on the crystal structures of MxA and elucidated how these mutations specifically affect the structure and therefore the function of MxA protein.
Cancer-associated Mx1 mutations were collected and screened from the COSMIC database. Twenty-two unique mutations that cause single amino acid alterations in the MxA protein were chosen for the analysis. Amino acid sequence alignment was performed using Clustal W to check the conservation level of mutation sites in Mx proteins and dynamins. Structural analysis of the mutants was carried out with Coot. Structural models of selected mutants were generated by the SWISS-MODEL server for comparison with the corresponding non-mutated structures. All structural figures were generated using PyMOL.
We analyzed the conservation level of the single-point mutation sites and mapped them on different domains of MxA. Through individual structural analysis, we found that some mutations severely affect the stability and function of MxA either by disrupting the intra-/inter-molecular interactions supported by the original residues or by incurring unfavorable configuration alterations, whereas other mutations lead to gentle or no interference to the protein stability and function because of positions or polarity features. The potential clinical value of the mutations that lead to drastic influence on MxA protein is also assessed.
Among all of the reported tumor-associated single-point mutations, seven of them notably affect the structure and function of MxA and therefore deserve more attention with respect to potential clinical applications. Our research provides an example for systematic analysis and consequence evaluation of single-point mutations on a given cancer-related protein.
The myxovirus resistance 1 (Mx1) gene is one of the most prominent interferon (IFN)-stimulated genes in vertebrate that are highly activated when triggered by type I and III IFNs upon viral infection. Human Mx1 is located on chromosome 21 and encodes the myxovirus resistant protein A (MxA) protein, which is a major antiviral factor against a wide spectrum of RNA viruses, such as influenza virus and Thogotovirus [1, 2]. The 78-kDa MxA protein is a member of the dynamin superfamily of multi-domain GTPases whose function relies on oligomerization and GTP hydrolysis . MxA has an N-terminal GTPase (G) domain, a stalk region responsible for oligomerization, a bundle-signaling-element domain (BSE) crucial for the communication between the G domain and the stalk region [4–6], and a 40-amino-acid-long loop (conventionally named L4) amid the Stalk on primary structure correlated with the pleckstrin homology (PH) domain in dynamin . Besides, MxA possesses a disordered loop at the N-terminus that is not conserved within the dynamin superfamily. According to the current working model, MxA forms ring-like oligomers around viral ribonucleoparticles (RNPs) and disrupts the structure of RNPs via conformational changes induced by GTP hydrolysis .
Apart from its role as a prominent antiviral protein in innate immunity, MxA has been found to be associated with different types of human cancer. It has been reported that the deletion of Mx1 gene, as a consequence of certain gene fusion events, is closely related to prostate cancer with a high aggressive tendency . Other studies of prostate cancer have suggested that the expression of MxA is suppressed in the highly metastatic human prostate carcinoma cell line PC-3M, and exogenous MxA can inhibit the mobility and invasiveness of PC-3M cells both in vivo and in vitro . Prostate cancer cells in which the Mx1 gene is knocked out have been shown to be much less sensitive to docetaxel compared with MxA-positive cells . The Mx1 gene has been found to be hypermethylated and suppressed in primary head and neck squamous cell carcinoma cell lines and tissue samples compared with normal lymphocytes . These studies indicate that Mx1 is a potential tumor suppressor gene. On the other hand, as a traditional immunotherapeutic reagent , type I IFNs are widely used in clinical treatments against a number of human cancers, including renal cell carcinoma, follicular lymphoma, melanoma, and chronic myelogenous leukemia . The effect of type III IFNs against different human cancers, including bladder carcinoma, Burkitt’s lymphoma, colorectal carcinoma, non-small cell lung cancer, and esophageal carcinoma, has also been investigated [13, 14]. As a key cytokine induced by types I and III IFNs, MxA is thought to be a useful biomarker for monitoring IFN activity and predicting clinical efficacy during IFN therapy in patients bearing certain types of cancer [15, 16]. A clinical study on early stage B cell chronic lymphocytic leukemia has suggested that patients with no MxA expression are likely to demonstrate a positive response to IFN therapy . Moreover, the expression level of MxA is also employed to predict the efficacy of chemotherapy on several types of cancer. A worldwide multi-center study has indicated that robust MxA expression is a positive indicator for patients with breast carcinoma who might benefit from anthracycline-based chemotherapy .
In recent years, with the development of next-generation sequencing technique and its wide application in cancer studies , the landscape of somatic mutations has been revealed for many types of human cancer. According to these comprehensive data sets, Mx1 mutations have been discovered in a number of common cancer types, including colorectal cancer [19–22], head and neck squamous cell carcinoma , follicular lymphoma , cutaneous squamous cell carcinoma , mantle cell lymphoma , embryonal rhabdomyosarcoma , renal cell carcinoma , prostate cancer , lung adenocarcinoma , melanoma , medulloblastoma , and ovarian carcinoma . Given the potential importance of MxA in tumorigenesis and metastasis as well as in the treatment and prognosis of different cancers, additional efforts are needed to investigate the biological associations between Mx1 mutations, especially the mutations that lead to the malfunction of its encoded protein MxA, and corresponding cancers. Mutations in coding regions can result in different consequences to the translated polypeptides, of which single amino acid alterations take up a considerable portion. These single-point mutations may give rise to various consequences to the function of MxA which, however, are difficult to be predicted and evaluated from the analysis of primary structure. In this study, we exploit the crystal structures of MxA and illustrate how these mutations specifically affect the structure and thus the function of MxA protein.
Information on cancer-related mutations in human Mx1 gene was collected from the Catalogue of Somatic Mutations in Cancer (COSMIC) database . All mutations were manually screened and only the mutations that cause single amino acid alterations in MxA were chosen for subsequent analysis.
Amino acid sequences of Homo sapiens (hs) MxA (UniProt code P20591) and MxB (P20592), Mus musculus (mm) Mx1 (P09922) and Mx2 (Q9WVP9), Gallus gallus (gg) Mx protein (Q90597), Danio rerio (dr) MxA protein (Q8JH68), Homo sapiens dynamin1 (Q05193), dynamin2 (P50570), and dynamin3 (Q9UQ16), Drosophila melanogaster (dm) dynamin (P27619), Caenorhabditis elegans (ce) dynamin (Q9U9I9), and Saccharomyces cerevisiae (sc) dynamin-related protein DNM1 (P54861) were aligned using Clustal W  and manually adjusted for non-conserved loop regions.
Crystal structures of full-length MxA (PDB code 3SZR), MxA Stalk (3LJB), apo MxA G domain-BSE fusion construct (Stalkless MxA) (4P4U), and Stalkless MxA complexed with β,γ-methyleneguanosine 5′-triphosphate (GMPPCP, a non-hydrolysable GTP analogue) (4P4S) were used as reference structures. For optimal accuracy, the resolution was considered a prior factor during the selection of reference structures comprising corresponding mutated residues. For mutations within the G domain, the crystal structure of apo Stalkless MxA (1.9 Å resolution) was applied as reference with the exception of L95P and P96S on Switch I. For these two mutations, the GMPPCP-bound Stalkless MxA structure (3.3 Å) was taken as reference because only when a GTP analogue is bound to the G domain can Switch I be ordered and fully observable. For mutations in the stalk region, the MxA Stalk structure (2.4 Å) was used for structural analysis. For mutations in BSE and Hinge 1, the full-length MxA structure (3.5 Å) was the only choice because other published structural models do not contain these residues. Structural analysis for all mutations was performed using Coot . Interactions among the residues were defined by the linear distance between the centers of the corresponding atoms in the reference models: 2.7–3.5 Å for hydrogen bonds and within 4 Å for salt bridges and hydrophobic interactions. Overall, all reference models provided sufficient information needed for reliable structural analysis.
Structural modeling of the mutants
Structural models of selected cancer-associated single-point mutants were calculated by the SWISS-MODEL server . In the amino acid sequence input files for each MxA mutant, the original residue was substituted by the post-mutation residue. Mutated MxA sequences were then individually uploaded to the SWISS-MODEL server for model calculation. The templates used for structural model building were assigned according to the corresponding reference models for each mutant as previously mentioned. In the output models, the residues that were absent in the original templates were removed for better quality because these parts may contain severe errors as a result of lacking reference information. The final structural models of the mutants were individually superimposed on the corresponding original reference models using Coot, and the root mean square deviation (r. m. s. d.) values for steric positions of the corresponding atoms between each model pairs were subsequently calculated.
Structural figure preparation
All structural figures were generated using PyMOL . Different types of atoms in stick or sphere representations were specified by the following colors: red for oxygen, blue for nitrogen, magenta for phosphorous, light green for magnesium, green for sulfur, yellow for carbon in residues that are mutated in human cancers, and gray for carbon in other amino acids that interact with residues of interest in this study. The spheres in the illustration represented Cα of the corresponding residues.
Overview of single-point mutations in MxA in different types of cancer
Summary of reported human myxovirus resistant protein A (MxA) single-point mutations in human cancers
S134L, N491K, R522C, T651M, R654Q, V263M, Y538C, S572Y, R655C (2)a
Head and neck squamous cell carcinoma
Cutaneous squamous cell carcinoma
L95P, P96S, P218S
Mantle cell lymphoma
Renal cell carcinoma
Distribution of cancer-related single-point mutations in MxA
Domain distribution of cancer-related MxA single-point mutations
Mutation(s) in cancers
GTPase domain (G domain)
L95P, P96S, S134L, P218S, V263M, R310S, K326N
Bundle-signaling-element domain (BSE)
L643V, R649W, T651M, R654Q, R655C
G392V, V449G, N491K, R522C, L619I
G540D, Y538C, S572Y
Single-point mutations in G domain
The G domain of MxA is responsible for GTP hydrolysis, as well as for the inter-ring homo-dimerization via the nucleotide-binding pocket . Both actions are crucial for the mechano-chemical coupling of the entire oligomer and thus for the function of the protein [5, 6].
S134L mutation occurs between the extra β-strand 1 (βE1 G ) and extra α-helix (αE G ) of MxA (Fig. 3c). As the polar S134 is located on the surface of the molecule, and its side chain also protrudes outward, its mutation to hydrophobic leucine would not influence the global folding of the G domain, but just slightly change the surface entropy of the molecule.
P218S mutation emerges between β-strand 4 (β4 G ) and α-helix 3 of the G domain (α3 G ). P218 terminates β4 G and turns the polypeptide chain to the opposite direction (Fig. 3d). Analogous to P96S, P218S may change the original trajectory of the following loop and therefore affect the folding of the protein.
V263 is surrounded by several other hydrophobic residues, including I223, L246, V264, and V268 (Fig. 3e). Compared with the hydrophobic pocket engulfing L95, the hydrophobic environment around V263 is much less extensive. As methionine is also a nonpolar residue, V263M mutation makes no alteration of the hydrophobic property of this area. Although methionine is physically a bulkier residue than valine, there is enough space at the top of V263 to accommodate a methionine side chain. Therefore, V263M mutation would cause very limited influence to the folding and stability of the protein.
R310 sits on the surface of the molecule. The side chain of R310 points outward and is quite flexible, as two conformations can be observed in the crystal structure, which suggests that this residue is not bound by any side-chain interaction from other parts of the protein (Fig. 3f). In this situation, its mutation to a polar serine residue will neither break any intra-molecular associations nor drastically change the surface polarity of MxA. Although R310S causes the loss of some positive charge, this mutation would not negatively affect the function of the protein.
K326 is located in α-helix 5 of the G domain (α5 G ) and also has an outward side-chain conformation. It forms a hydrogen bond with the oxygen of K273 and additionally a weak salt bridge with E330 which also sits in α5 G (Fig. 3f). The K326 N mutation may not substantially affect these two interactions, as asparagine also has a polar side chain that can form hydrogen bonds with K273 and E330. Therefore, it is very likely that this mutation does not give rise to any major disruptions of MxA structure.
Single-point mutations in BSE
In addition to its role as an intra-molecular messenger, BSE also contributes to the formation of functional homo-oligomers, which is a fundamental feature of dynamin superfamily members (Fig. 4b). R654 participates in BSE-Stalk interaction between parallel MxA monomers via a charged interaction with D478 on the other molecule (Fig. 4c). Disruption of this salt bridge by a D478A mutation results in abnormal GTPase activity and weakened oligomerization and antiviral abilities . Not surprisingly, the colorectal cancer-associated R654Q mutation, which abolishes the D478-R654 salt bridge, should have a similar effect. On the other hand, glutamine still possesses the tendency to form a hydrogen bond with D478, and this can be deemed as a compensation for the loss of the salt bridge. As a result, this mutant would hardly cause negative consequence to MxA compared with the reported D478 mutant.
Single-point mutation in Hinge 1
Single-point mutations in the stalk region
On the other hand, three additional single-point mutations that are not involved in any oligomerization interfaces have been discovered in the stalk region. N491 is a surface-located residue situated on the α-helix 2 of Stalk (α2 S ), forming a hydrogen bond with D385 on the parallel α-helix 1N-terminal part (α1N S ) (Fig. 6c). Its mutation to positively charged arginine may strengthen this interaction, as a salt bridge can be thus introduced. Therefore, this single-point mutation would play an insignificant role in tumorigenesis or in the development of colorectal cancer . Another colorectal cancer-related mutation site, R522, is also a solvent-exposed residue on α3 S . This residue, together with three neighboring negatively charged glutamates (E466 and E467 on α2 S , and E518 on α3 S ), constitutes a vast network of charged interactions endorsed by the salt bridges, in which R522 is at the center, to provide positive charge (Fig. 6d). It is imaginable that its mutation to weak polar cysteine causes the absence of the pivotal positive charge and lead to interference of electrostatic balance on the protein surface. In this case, the folding and stability of the whole protein would become adversely influenced. Unlike N491 and R522, L619 located on α4 S possesses an inward side chain conformation. It is part of a local hydrophobic core that includes L498 on α3 S , M616 on α4 S , and L629 on α5 S . When mutated to isoleucine, a derivative comparable to leucine itself in both size and charge, the residue can still stably reside in and maintain this environment. As a result, this ovarian carcinoma-associated mutation L619I will lead to hardly detectable structural and functional aberrance to MxA.
Single-point mutations in the N′-loop and L4
The N′-loop and L4 are both intrinsically disordered loops that lack intra-molecular interactions with other residues, and therefore, it is impractical to observe them in crystal structures. The N′-loop is not conserved among Mx proteins, and its length varies among different species. This region was recently reported to be involved in the specification of viral targets . Given the similar properties of threonine and serine, the T27S mutant would not chemically differ from wild-type MxA, but it is unpredictable whether this mutation would affect the protein’s interaction with viral structures. L4 is essential for membrane binding and viral resistance by direct interaction [46, 47]. However, currently only several residues in the middle of L4, but not Y538, G540, or S572, were proven to be functionally important for MxA [4, 47]. Therefore, it is difficult to predict the influence of these three mutations on MxA function, although they are not likely to disrupt the flexible conformation of L4.
As next-generation sequencing data of different human cancers continue to accumulate, abounding tumor-associated mutations of various types are being discovered and further analyzed. Compared with frame shift and stop codon mutations in the coding regions of given genes, it is more tricky to judge the effect of single amino acid alterations on the physiological properties of the proteins. In principal, functional proteins entail orchestrated intra-molecular interactions of the component residues and proper folding of entire polypeptide chains, which can be substantiated as so-called protein structures. In regards to analyses of single-point mutations, if the structures of the corresponding proteins have been solved by X-ray crystallography or other techniques with a decent resolution, the prediction of the effects of these mutations becomes much more reliable.
Summary of the structural analysis of cancer-related MxA single-point mutations
Position in protein
Polarity before mutation
Polarity after mutation
Very moderate mutations
According to our analysis, besides proline- and glycine-related mutations, other mutations cannot be associated with influencing levels only by single factor (position or chemical properties) (Table 3). To provide a more intuitionistic view of how these mutations may affect the structure of MxA, we performed modeling of several mutants selected from all four groups, and compared the output models to the original crystal structures. However, the calculated mutant models just bear tiny variations compared with the corresponding original structures (r. m. s. d. values less than 0.1 Å). The reason is that current structure prediction algorithms rely on the primary sequence alignment of reference structures, and differences for amino acids in stereochemistry and polarity are not taken into account during model calculation. Therefore, analyzing single-point mutations requires careful and comprehensive manual considerations in multiple aspects involving chemical properties of specific amino acid residues as well as those of the whole protein.
The seven drastic MxA mutations found in this study (L95P, P96S, G392V, V449G, P218S, R522C, and E632K) are likely to play important roles in tumorigenesis and development of corresponding human cancers, and therefore evolve to effective tumor-related biomarkers, although more biochemical and cellular assays are needed for their potential clinical applications. Moreover, it is noteworthy that all three cutaneous squamous cell carcinoma-related mutations (L95P, P96S, and P218S) lead to remarkable disruption of the protein structure, suggesting a strong association between this cancer type and MxA. Finally, our systematic approaches of structure-based analysis for single-point mutations in MxA protein are widely applicable to the evaluation of outcomes of mutations in different types of cancer for those proteins with available structural information.
In this study, by analyzing 22 unique tumor-associated mutations in the human MxA protein by structural methods, we found that 7 out of 22 mutations have a high propensity to affect tumorigenesis and the development of corresponding cancers. These seven mutations are therefore more prone to potential clinical application as useful biomarkers. In addition, our research provides a good example for thorough analysis and consequence evaluation of single-point mutations on a given cancer-related protein.
J-LH, Y-JH, YC, and SG conceived the project, analyzed the data, and wrote the manuscript. J-LH, Y-JH, YC, and BY performed experiments. All authors read and approved the final manuscript.
This work was supported by research grants from the National Natural Science Foundation of China (No. 31200553), the National Basic Research Program of China (No. 2013CB910500), the Program of New Century Excellent Talents in University (NCET-12-0567), and the Recruitment Program for Young Professionals.
We thank Prof. Chao-Nan Qian for the help during manuscript preparation.
Compliance with ethical guidelines
Competing interests The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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