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Contains a Metalloprotease and a Disintegrin Domain Proc. Natl. Acad. Sci. USA Vol. 90, pp. 10783-10787, November 1993 Developmental Biology The precursor region of a protein active in sperm-egg fusion contains a metalloprotease and a disintegrin domain: Structural, functional, and evolutionary implications (PH-30/spermatogenesis/snake venom/astacin/celi adhesion) TYRA G. WOLFSBERGt4, J. FERNANDO BAZANt§, CARL P. BLOBELt$¶, DIANA G. MYLESII, PAUL PRIMAKOFFII, AND JUDITH M. WHITEtt** Departments of tPharmacology and tBiochemistry and Biophysics, University of California, San Francisco, CA 94143; and IlDepartment of Physiology, University of Connecticut Health Center, Farmington, CT 06030 Communicated by Bruce M. Alberts, August 4, 1993 ABSTRACT PH-30, a sperm surface protein involved in quences of the remainder of the a precursor region and the sperm-egg fusion, is composed oftwo subunits, a and (3, which entire ( precursor region were determined from clones of a are synthesized as precursors and processed, during sperm and (8 isolated at high stringency (3) from a guinea pig development, to yield the mature forms. The mature PH-30 whole-testis cDNA library (8). a/fl complex resembles certain viral fusion proteins in mem- Northern Analysis. RNA was isolated from adult male brane topology and predicted binding and fusion functions. guinea pig tissues (9), electrophoresed in a formaldehyde/ Furthermore, the mature subunits are similar in sequence to agarose gel, and transferred and cross-linked to a Hybond-N each other and to a family of disintegrin domain-containing nylon membrane (Amersham). High-stringency prehybrid- snake venom proteins. We report here the sequences of the ization and hybridization with-PH-30 a and 3832P-labeled PH-30 a and (3 precursor regions. Their domain organizations DNA probes was carried out at 65°C in 5x standard saline are similar to each other and to precursors of snake venom citrate (SSC)/5x Denhardt's solution/0.1% SDS containing metalloproteases and disintegrins. The a precursor region salmon sperm DNA at 0.2 mg/ml. The membrane was contains, from amino to carboxyl terminus, pro, metallopro- washed, 10 min per wash, in 2 x SSC/0.1% SDS once at room tease, and disintegrin domains. The ,B precursor region con- temperature and twice at 65°C and then in 0.2x SSC/0.1% tains pro and metafloprotease domains. Residues diagnostic of SDS twice at 65°C. Hybridization with a mouse f-actin probe a catalytically active metalloprotease are present in the a, but was carried out in the same solution at 55°C, with identical not the ,B, precursor region. We propose that the active sites of wash conditions. the PH-30 a and snake venom metalloproteases are structurally similar to that of astacin. PH-30, acting through its metallo- AND protease and/or disintegrin domains, could be involved in RESULTS DISCUSSION sperm development as well as sperm-egg binding and fusion. The amino acid sequences of the PH-30 a and (3 precursor Phylogenetic analysis indicates that PH-30 stems from a mul- regions were deduced from cDNA sequences and are shown tidomain ancestral protein. in Fig. 1. Following their signal sequences, the a and P precursor regions contain sequences similar to those in the PH-30, a guinea pig sperm surface protein, is a candidate prodomains of disintegrin domain-containing snake venom sperm-egg membrane binding and fusion protein (1-5). The proteins, and then sequences which align with the snake PH-30 subunits found on fertilization-competent sperm, mature venom zinc-dependent metalloprotease domain (Figs. 1 and a and mature (, share membrane topologies and other charac- 2). a contains the consensus active-site residues for a me- teristics with viral binding and fusion proteins. The (3 subunit talloprotease (see below); (3 does not. Following the metal- contains a potential receptor binding domain, a disintegrin loprotease domain, both proteins contain a disintegrin do- domain, related to soluble integrin ligands found in snake main (Figs. 1 and 2). The cleavage site which generates venom. The a subunit contains a potential fusion peptide. In mature a falls within the disintegrin domain (3) (arrows, Figs. addition, the two subunits share sequence similarity. 1 and 2). The cleavage site which generates mature , lies at Snake venom disintegrins derive from precursors that also the amino terminus of the disintegrin domain (3) (arrow contain zinc-dependent metalloprotease domains (6, 7). In- before position 383, Figs. 1 and 2). The sequence alignment terestingly, PH-30 a and , are present on testicular sper- of mature PH-30 a and 8 with the snake venom proteins matogenic cells as larger precursors, termed here pro-a and continues through the cysteine-rich domain (Figs. 1 and 2). pro-,8 (2). Here we show that the precursor regions of PH-30 No snake venom proteins include either the epidermal growth a and 3 (the regions amino-terminal to the mature proteins factor repeat or the transmembrane and cytoplasmic seg- and found on developing, but not fertilization-competent, ments of a and (3(Figs. 1 and 2). Additional mammalian genes sperm) share further amino acid identity with each other as encode proteins with domain organizations identical to those well as with this family of metalloprotease and disintegrin of PH-30 a and 8 (Figs. 1 and 2). EAP I, cloned from rat and domain-containing snake venom proteins.tt monkey, is an androgen-regulated protein located on the apical surface of epididymal epithelial cells (13). Cyritestin is MATERIALS AND METHODS a mouse testis cDNA (GenBank accession no. X64227). Cloning. A portion of the a precursor region sequence was obtained from a PCR product generated by the nested RACE §Present address: Department of Molecular Biology, DNAX, Palo (rapid amplification of cDNA ends) protocol (3). The se- Alto, CA 94304. lPresent address: Department ofCellular Biochemistry and Biophys- ics, Sloan-Kettering Institute, New York, NY 10021. The publication costs of this article were defrayed in part by page charge **To whom reprint requests should be addressed. payment. This article must therefore be hereby marked "advertisement" ttThe sequences reported in this paper have been deposited in the in accordance with 18 U.S.C. §1734 solely to indicate this fact. GenBank data base (accession nos. Z11719 and Z11720). 10783 Downloaded by guest on September 27, 2021 10784 Developmental Biology: Wolfsberg et at. Proc. Natl. Acad. Sci. USA 90 (1993) PH 3I a N R S 0 S M M A V P N T I S F S A S C Q K A H V V L HV A R S L L Q T C T L L MV A P R L 0 L V P 0 HL C V R L V T K LL V 0 TV L L P H IOH CH C G P V 78 PH 30 P ~' M LC LLL L LCOCL ACO1OGP.L KK YV 22 Cyritestoon M A A ALFFL; L 0 Y CDGQVI AtA OK D V 22 EA;P I M F P T 0 I F L H $ V L I S QMH 0G KG I:V G VE t, Q K L V H P K 33 Ht-e MI QV LCLV T I CLAAF PY QOG'SSISILE SOGN VN D 30 TrigraaS4n M I QV L COIT I C L A VFPP Y QOGVI SOIIL E S ON C N D 30 PH 30 aE H Y SIX ElI V IP E S L T V K 0 S Q -D POO R TOSY ML LI QWH K IHL RDEVDDP Y1-HHN DKTI OAR DC.. H Y 152 PH-30 E NOON QITDO V P K K I RS V K KG - -S V K S E VI - K IV OKE NT T YII V N L V R K H F L P HD F Q VY SWO I AIoI H K P F K DY S Q N F C IYI 96 Cyritestin K T P L Q rTI V F E K ID TOIl IQD AF KE AKE T Q V T Y V V T I EGKOA Y T L LKE K I sIFIL H P L F 0 T Y L R D K LWT L Q P YF IL V KT H:C FlY 98 KAP I K L S L L Q Y RD L K K I H C S D T P EK KY K K K L L YE I KL -OGR K T L T LH L L P A K KIFIL A L NY I K T YIYN IK K K MV T K H P QI LD H :C FFll 109 Jararhagin A TR P KOA V IP -K Y EDLA M QY E FYV NOKEPIV% L HLEFKN KOGLFISKODlIE IHY SP DOR EOIT TYP P VKEDHCYYI 69 E R Q G K Y - TriaramirHr a YK V VYPIPY PVV T A L P KP0 A V FYIEK Y KMD A YMKYK F P V NN-OKE0E P V,V VLC_ H L K N K L IE & D -10£EY I HY IS D OKKE I T A IP I V K D H C YMlj S A I L K H T A A P A K D SQ A V S 225 PH830 at EW ISP C Q ENT TIS-V Y KI LIWISQP VLIY-- K RD Y VSERA K TO HIDQ PH20 I 0 H I K F F T I A I I I L R 0 L L F K 0 O I K P SIS I 0 F K H V I I P V H DN K K S I S I N V K N V V Y I K I I ---171 Cyritestin Q101N A A0~~~JElI FY TVT LITTOCADGC I L ROCL L Q L EN I21T1Y1K PLF LKE I IIA T F E HOI LY EIOKNNKKID Y I F LCHKKEKN F A N I K 1 11Y1KQ 0 LIE 1716 KAFO QGIISfH E F It' ~A I TOCNIGLIR GIF F R JNDIQRHYL OKE V K YWSD K 0 DIHI L V F K I NV K A P Y A T N ISOE 0 L N K T K K I T C I D A K 0 086 Jararhagmn H INK DA D ST ASI S ACN GL K 0 Y F K LIQR E T YF OK FL F L F DOSE AJHA I FFKY E NV EK ED K A PfrMHfGJV T QNWEK S Y E POIXKE A S 044 HI-e NOGR OKE N D A DS T A I I I AINOG L F O H F E LGOMNYCL I K F L K LD S K A H A I F K L K N I K K K D K A P KM C G V T QN W El SEP IKEK A S 183 Trigramin HOE-IR N D ADS TA IACDIG CFK OH F E L 0KEM SCL I K P C E LCWD S K A H A I F K I E NV E KE D K P PWM CJG V T IN W El I K S T K K A S 183 Metalloprotease Domain PH-3S ax 00 P P: P H S V~Q A C I I I CV..N T KHn,VWHE F V VH N00 IRK I H WDGSDV OlNE TIDWEV V D II A L A Nl F TED I N T EHVIH A 0 V EWVHT EDG 301 P9-30 p - -P0---------KSS V P T H WO NL~ HO ILLE N LIP H MOO N T AT V T EK IFO Q L VOCL N N A F FSTTWN L T VOAILA L WID E 234 Cyritestin P EK GOS ----------N S T L T KF PILE OIK ION D F A M F O HM 0 K OVGVA T QK V V HOPF LOI NIT H FQI ILI M T VMLNN L EIIWOI I 244 EAP 0 0 K K H F V K 3 H K K K F oW'L F V VWADIE F V; S R K N I K P Q N K C R KI H0WGMVIN P VIHIH I IYKA ILIN 0 K V T L T 0 M EIKWII A 0 255 Jararhagin ICL A FPT A -K-- I RIDr P YK KYI F P VV V 000 T VT K NNOG DCL D K OKX A R H YE L AN I VWKE OFRK SYHMHWIVIA VOGLCIKWIN 0 225 TrigraRin Q C N T P K -'--- 2 Q H F P Q RIOtI C 0G P- V 0 H 0 M S T K 1 0 0 N S KH I T K RIV H IH I N N OWFN H I K AWF]N I I T T CLS V C K I W S EKF 253 PH-30 aE WCHIE V P V OR V IIN F1N RERI D FHLL PRN RH DVWAH M I 'OGH H P0-KE T SWIWQF LCNO AtC SlOPC A A A 1KE A P H H ED A LCCI A A C C 37H PHlI II OD E EI VC V RSPI10IR M:IC.
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