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Internal Duplication and Evolution of Human Ceruloplasmin (Protein Structure/Internal Homology/Gene Evolution/Copper Oxidases/Ferroxidase) FRANCIS E

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Internal Duplication and Evolution of Human Ceruloplasmin (Protein Structure/Internal Homology/Gene Evolution/Copper Oxidases/Ferroxidase) FRANCIS E Proc. Nati. Acad. Sci. USA Vol. 78, No. 5, pp. 2805-2809, May 1981 Biochemistry Internal duplication and evolution of human ceruloplasmin (protein structure/internal homology/gene evolution/copper oxidases/ferroxidase) FRANCIS E. DWULET* AND FRANK W. PUTNAMt Department of Biology, Indiana University, Bloomington, Indiana 47405 Contributed by Frank W. Putnam, January 29, 1981 ABSTRACT With ihe completion of the primary structure of which guided our sequence determination, and we noted sig- the 50,000- and 19,000-dalton fragments ofhuman ceruloplasmin nificant homology to other copper-containing proteins (10). This [ferroxidase; iron(il):oxygen oxidoreductase, EC 1.16.3.11], over report presents evidence for these observations and offers a halfofthe covalent structure ofthe single polypeptide chain ofthis model for the evolutionary development of ceruloplasmin and protein is known. Visual and computer analysis of the sequence other multicopper oxidases. of the 564 amino acid residues in the two fragments gives clear evidence of statistically significant internal homology suggestive of evolutionary replication of two smaller units. Two homology METHODS regions, each composed of 224 residues, were defined by an in- During the course ofsequence analysis ofthe 50-kDal fragment trasequence alignment that required only three gaps in each 224- it became apparent that many peptides were homologous to residue segment. The two homology regions exhibited 43% iden- segments ofsequence in the 19-kDal fragment (10). In fact, the tity in sequence, and 13% of the remaining positions had similar placement ofmany peptides in the final sequence ofthe 50-kDal residues. The sequence ofa 160-residue segment in ceruloplasmin fragment was predicted from this homology. On completion of exhibits significant homology to the active (copper-binding) sites the sequence a search for intrasequence homology within the of blue electron-transfer proteins such as azurins and plastocy- 50-kDal fragment and for intersequence homology between the anins and multicopper oxidases such as cytochrome oxidase and two fragments was made by manual alignment ofshort segments superoxide dismutase. It is proposed that a primitive ceruloplas- against the entire structure until the optimal fit was found. This min gene was formed by the fusion of two genes coding, respec- led to the alignment in Fig. 1, in which the carboxy-terminal tively, for proteins about 160 and 190 amino acid residues in length 65 amino acids of the 50-kDal fragment followed by the 159 in and that this precursor gene coding for about 350 amino acids was the 19-kDal fragment are aligned with positions 1-224 of the later triplicated to form the gene for the present-day ceruloplas- 50-kDal fragment, leaving an unmatched stretch of 116 amino min molecule of about 1050 amino acids. acids. Analytical and statistical comparison of amino acid sequences In order to test the validity ofthe alignment in Fig. 1 and to has been a powerful method for detection and estimation of evaluate its statistical significance, the consecutive sequences structural similarities among and within proteins, for evaluation ofthe 50-kDal and 19-kDal fragments (564 residues) were sub- of structure-function relationships in a family of proteins, and jected to a search for intrasequence homology by using the pro- for study of genetic change in the course of evolutionary de- gram RELATE ofthe Atlas ofProtein Sequence and Structure velopment of a class ofproteins (1-3). The comparison may be (5). This program compares all possible segments of a given done by visual alignment oftwo sequences for best fit as judged length (in this case, 25 residues) both in the real sequence and both by identity and similarity of paired amino acids at corre- in 100 random runs, and, using a mutation data matrix for all sponding positions; gaps in the sequences are sometimes in- possible pairs of amino acids, it accumulates segment scores. serted to maximize the fit. Statistical methods for assessing re- The mean ofa predetermined numberofhighest segment scores latedness of proteins are based on computer programs that is expressed in standard deviation (SD) units. Also, by use of accumulate pair scores for two amino acids, using a mutation the program SEARCH, selected 25-residue segments ofthe 50- data matrix based on physical and structural parametersg and kDal and 19-kDal sequences were compared with all known codon differences for all possible pairs ofamino acids (4) or from protein sequences to seek hints of evolutionary similarity. The actual accepted point mutations accumulated from related se- amino-terminal sequence ofthe single-chain molecule (11) was quences (5). By such means the degree ofintersequence or in- also compared with the entire 564-residue sequence to identify trasequence homology may be assessed; here "homologous" is additional internal homology. These searches were done by W. used to mean matching (identical or similar) in structure, po- C. Barker of the National Biomedical Research Foundation, sition, physical characteristics, and codons. Washington, DC. With the recent completion ofthe primary structures of the 50,000-dalton (50-kDal) (6) and 19,000-dalton (19-kDal) (7-9) RESULTS AND DISCUSSION fragments ofhuman ceruloplasmin [ferroxidase; iron(II):oxygen When the primary structures of the 50-kDal and 19-kDal frag- oxidoreductase, EC 1.16.3.1], 564 residues of the amino acid ments are aligned as in Fig. 1, two long regions of homologous sequence of the single polypeptide chain of this protein are sequences are readily identified, which suggest an internal du- known. These fragments are from the carboxyl terminus of the plication. We call the two regions homology segments; they are molecule and account for more than halfofthe primary structure defined by aligning residues 1-224 ofthe 50-kDal fragment with of this blue copper oxidase. During our study we identified a residues 341-405 ofthe 50-kDal fragment immediately followed remarkable degree of internal homology in ceruloplasmin, Abbreviation: kDal, kilodalton(s) The publication costs ofthis article were defrayed in part by page charge * Present address: Department of Medicine, Indiana University, In- payment. This article must therefore be hereby marked "advertise- dianapolis, IN 46223. ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. t To whom reprint requests should be addressed. 2805 Downloaded by guest on September 26, 2021 2806 Biochemistry: Dwulet and Putnam Proc. Natl. Acad. Sci. USA 78 (1981) Ser-Val-Pro-Pro-Ser-Ala-Ser-His-Val-Ala Pro Thr-Glu-Thr Phe. Thr-TyrGlu Trp Thr-Val Pro Lys-Glu-Val Gly Pro-Thr-Asn-Ala- 341 i5LL i 360 j370 Thr-Glu-Ser-Ser-Thr-Val-Thr-Pro-Thr-Leu Pro Gly Glu-Thr Leu Thr-Tyr]Val Trp Lys-Ile Pro Glu-Arg-Ser Gly Ala-Gly-Thr-Glu- 17 ~~~~~~~~~4050 (60 Asp Pro-Val Cys Leu-Ala-Lys-Met Tyr-Tyr-Ser Ala Val-Asp Pro-Thr Lys-Asp Ile-Phe-Thr Gly-Leu-Ile-Gly-Pro Met-Lys-Ile Cys Tyr-Tyr-Ser Thr Gln-Val Lys-Asp Leu-Tyr-Ser Leu-Ile-Val 400Cy Asp Ser-Ala CysLIIle-Pro-Trp-Ala 380jj,380390Val-Asp{J Gly-Leu-Ile-Giy-Pro 70 80 ~~~~~~~~~~~{90 Lys-Lys-Gly-SerLuhHis-Ala|,GlyAGlnyAsp-Val-Asp-LysG Tyr Leu Phe-Pro-Thr Val-Phe-Asp-Glu-Asn-Glu-Ser} 405 1 1 20 Arg-Arg-Pro-Tyr Le'Val-Phe Asn Po Arg Arg Ly--- Leu - Glu-Phe Ala Leu Leu-Phe-Leu Val-Phe-Asp-Glu-Asn-Glu-Ser Leu-Leu Leu Glu Asp-Asn-Ile Arg-Met-Phe-Thr-Thr-Ala Pro Asp-Gin Val AspKLy Glu Asp-Glu Asp Phe Gln Glu-Ser-Asn-Lys-Met- 30 UU 40 U50 Trp-Tyr Leu Asp Asp-Asn-Ite Lys-Thr-Tyr-Ser-Asp-His Glu-Lys Aen Lye AsplAsp-GuC us PheI ie Glu-Ser-Asn-Lys-Met - Ser-Met Gln-Pro Cys-Lys Trp-Tyr-Leu Phe-Ser-Ala His Gly-Leu-Thr-Met Gly-Asp Asn-Gly-Phe171 171~~6Met Tyr Gly-Asn1300 O15Ser Val Val Gly- H Ala-Ile Asn-Gly ArMePhe1Gly-Asn1Leu-GZn Gly-Leu-Thr-Met His-Val Gly-Asp GUsVl AenTrp-r-Leu?Met-Gly-Met I L i U 60 801I0iy-70 L~~J Val --- --- --- Asn-Glu Ala Asp His Gly-Ile-Tyr Phe-SerGly Asn-Thr-Tyr-Leu-Trp Gy G1u-Arg-Arg Asp-Thr-Ala-Asn-Leu- 11.1 U 100 110 Asn-Giu lIe Leu Thr-Val-His8~~90 PheHisl Hi-Ser-Phe-Gln-Tyr-Lys-His Ag-Gly Val-Tyzr-Ser-Ase Val-Phe-Asp-Ile - Phe-Pro Gln Thr Ser-Leu Thr-Leu120His Met TrpU~~~~~4Pro Asp ThrGluUGly Thr-Phe-Asn-Val-GluCys~~130 uLi1j40Leu-Thr Thr-Asp-HissTyr-Thr-Gly- Phe-Pro Gly TTyr-Gin Thr-Leu GluMeheP Arg Pro GlyIiee-Trp-LT-eu-Leu-HisCs His-Val1Thr-As -His lie-His-Ala - r 1 2210 F1 220 230 |Gly-Met Lys-Gl n-Lys Tyr-Thr-Val Asn Gln Cys-Arg-Arg-Gl n-Ser-Glu-Asp-Ser-Thr-Phe-Tyr-Leu-Gly-Gl u-Arg-Thr-Tyr-Tyr-Iie-Al a - II lisolII~~15 159 |Gy-MetjGZ~u-Thr-ThrjTyr-Thr-ValZLeu Asn-Glu-Aap-Thr-Ly-Ser--Gly-COOH 240 250 260 4 Ala-Val -Gl u-Val -Gl u-Trp-Asp-Tyr-Ser-Pro-Gl n-Arg-Gl u-Trp-Glu-Lys-Gl u-Leu-Hi s-His-Leu-Gl n-Gl u-Gl n-Afi-Val -Ser-Asn-Al a-Phe- 270 280 290 Leu-Asp-Lys-Gly-Gl u-Phe-Tyr-I le-Gly-Ser-Lys-Tyr-Lys-Lys-Val -Val -Tyr-Arg-Gl n-Tyr-Thr-Asp-Ser-Thr-Phe-Arg-Val -Pro-Val -Gl u- 300 310 320 Arg-Lys-Al a-Gl u-G-lu-Gl u-Hi s-Leu-Gly-I le-Leu-Gly-Pro-Gln-Leu-Hlis-Al a-Asp-Val -Gly-Asp-Lys-Val -Lys-Ile-I le-Phe-Lys-Asn-Met- 330 340 Ala-Thr-Arg-Pro-Tyr-Ser-Ile-His-Ala-His-Gly-Val -Gln- FIG.
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