DeGroot MS , Williams B , Chang TY , Maas Gamboa ML , Larus IM , Hong G , Fromme JC , Liu J .

P40 OD010440 NIH HHS , R35 GM130351 NIGMS NIH HHS , R35 GM136258 NIGMS NIH HHS , S10 OD017992 NIH HHS

	Fig 1. SMOC-1::2xFLAG is fully functional. (A) Diagrams depicting the smoc-1::2xflag endogenous locus (jj276) and a transgene with 2 kb smoc-1 promoter and 2 kb smoc-1 3′ UTR flanking the smoc-1::2xflag genomic sequence. jjIs5798 and jjIs5799 are 2 integrated multicopy array lines that overexpress smoc-1::2xflag. In this and all subsequent figures, protein domains in SMOC-1 are indicated by color: SP, signal peptide, navy; TY, thyroglobulin-like domain, green; EC, extracellular calcium binding domain, blue; 2xFLAG, purple. Exons are represented by colored bars, while introns and intergenic regions are represented by thin black lines. (B) Western blot of 50 gravid adults of each indicated genotype, probed with anti-FLAG (top) and anti-actin antibodies (bottom). Full-length SMOC-1::2xFLAG at approximately 41 KDa (marked by a red *) is detectable in strains that overexpress SMOC-1::2xFLAG (jjIs5798 and jjIs5799), but not in WT controls nor in jj276 worms that expresses endogenous SMOC-1::2xFLAG. Black *s indicate nonspecific bands detected by the anti-FLAG antibody. (C) Relative body sizes of various strains at the same developmental stage (WT set to 1.0). jjIs5119 is an integrated multicopy array line that overexpresses untagged smoc-1. Groups marked with distinct symbols are significantly different from each other (P < 0.001, in all cases when there is a significant difference), while groups with the same symbol are not. Tested using an ANOVA with a Tukey HSD. WT: N = 65. ok3749: N = 38. tm7125: N = 36. jj276: N = 31. jjIs5119: N = 42. jjIs5798: N = 72. jjIs5799: N = 68. (D) Diagrams depicting the Susm phenotype used to test smoc-1 functionality. CCs are represented with green circles, with the 2 posterior M-derived CCs marked with pink arrowheads. (E) Table showing the penetrance of the Susm phenotype of various mutant strains. The Susm penetrance refers to the percentage of animals with 1 or 2 M-derived CCs as scored using the arIs37(secreted CC::GFP) reporter (see Materials and methods). For each genotype, the Susm data from 2 independent isolates (see S6 Table) were combined and presented in the table. a The lack of M-derived CCs phenotype is not fully penetrant in sma-9(cc604) mutants. b Data from DeGroot and colleagues [12]. Statistical analysis was conducted by comparing double mutant lines with the sma-9(cc604) single mutants. ***P < 0.001; ND: no difference (unpaired two-tailed Student’s t test). Original data sets are in S1 Data. CC, coelomocyte; SMOC, secreted modular calcium-binding protein; WT, wild type. https://doi.org/10.1371/journal.pbio.3002272.g001
	Fig 2. SMOC-1 interacts with LON-2 in worm extracts and in vitro. (A) Sequence of C. elegans LON-2 protein with peptide regions detected in the different IP/MS experiments marked. Peptides detected in the full-length SMOC-1::2xFLAG pulldown are underlined, while peptides detected in the SMOC-1(EC)::2xFLAG pulldown are in bold. Important regions of LON-2 are also highlighted, including the signal peptide (gray), RGD motif (orange), RLGR consensus putative furin protease recognition site (green), HS GAG attachment sites (aqua), and GPI linkage site (red). The 3 residues (S311, A315, and F319) in red boxes are predicted to mediate LON-2-SMOC-1 interaction and are mutated to generate the lon-2(mut) mutation described later. (B) Diagrams of the expression constructs used in the Drosophila S2 cell expression system. (C) Results of co-IP experiments testing the interaction of HA::LON-2 with different versions of SMOC-1::V5* produced in Drosophila S2 cells, including SMOC-1(Full)::V5, SMOC-1(TY)::V5, and SMOC-1(EC)::V5. IP with anti-V5 beads or anti-HA beads, IB with anti-HA or anti-V5 antibodies, as indicated. Experiments were independently repeated in triplicate, with representative results shown in this figure, and < points to faint bands that may represent glycosylated LON-2. We do not know whether posttranslational modification or cleavage causes SMOC-1 proteins to run as 2 bands when expressed in Drosophila S2 cells. Original images of western blots can be found in S1 Raw Images. co-IP, coimmunoprecipitation; EC, extracellular calcium-binding; GAG, glycosaminoglycan; HS, heparan sulfate; IB, immunoblot; IP, immunoprecipitation; SMOC, secreted modular calcium-binding protein; TY, thyroglobulin type-1. https://doi.org/10.1371/journal.pbio.3002272.g002
	Fig 3. The EC domain of SMOC-1 is sufficient to regulate BMP signaling when overexpressed. (A) Diagrams depicting the genomic constructs expressing full-length SMOC-1::2xFLAG (pMSD35), SMOC-1(TY)::2xFLAG (pMSD44), and SMOC-1(EC)::2xFLAG (pMSD45). All plasmids contain the same 2 kb promoter and 2 kb 3′ UTR of smoc-1. SMOC-1(TY) ends at amino acid 134, while SMOC-1(EC) starts at amino acid 135, both containing the same SMOC-1 SP, and the 2xFLAG tag. (B) Western blot of 50 gravid adults of each indicated genotype, probed with anti-FLAG (top) and anti-actin antibodies (bottom). The strain overexpressing full-length SMOC-1::2xFLAG (jjIs5799) is an integrated transgenic strain, while those overexpressing SMOC-1(TY)::2xFLAG (jjEx6089 and jjEx6090) or SMOC-1(EC)::2xFLAG (jjEx6052 and jjEx6093) carry the transgenes as extra chromosomal arrays, thus the expression level appeared lower due to random loss of the array during each mitotic division. (C) Relative body sizes of strains carrying indicated versions of smoc-1 as extra chromosomal arrays in a smoc-1(tm7125) null background at the same developmental stage (WT set to 1.0). For panels C and D, gray indicates non-transgenic worms that do not express any smoc-1. Two independent transgenic lines were measured and combined for each plasmid being tested here. Statistical analysis was done by comparing transgenic strains with non-transgenic counterparts. ***P < 0.001; *P < 0.01, ND: no difference (ANOVA followed by Tukey HSD). WT: N = 23. tm7125: N = 25. Full-length smoc-1 (transgenic: N = 44; non-transgenic: N = 41). smoc-1(TY) (transgenic: N = 40; non-transgenic: N = 39). smoc-1(EC) (transgenic: N = 66; non-transgenic: N = 47). (D) Summary of the Susm penetrance of strains carrying indicated versions of smoc-1 in a smoc-1(tm7125); sma-9(cc604) background. The Susm penetrance refers to the percent of animals with 1 or 2 M-derived CCs as scored using the arIs37(secreted CC::GFP) reporter. For each genotype, 2 independent isolates were generated (as shown in the strain list), the Susm data from the 2 isolates were combined and presented here. Number of animals scored are noted on each bar. Statistical analysis was done to compare transgenic strains with non-transgenic counterparts. See panel C for color legend. ***P < 0.001 (general linear model, Wald statistic). Original data sets are in S1 Data. Original images of western blots can be found in S1 Raw Images. BMP, bone morphogenetic protein; EC, extracellular calcium-binding; SMOC, secreted modular calcium-binding protein; SP, signal peptide; TY, thyroglobulin type-1; WT, wild type. https://doi.org/10.1371/journal.pbio.3002272.g003
	Fig 4. When expressed at the endogenous locus, neither SMOC-1(TY) nor SMOC-1(EC) is fully functional in regulating BMP signaling. (A) Diagrams depicting the full-length smoc-1, as well as truncated smoc-1(TY) and smoc-1(EC) at the endogenous locus. All of them are tagged with a 2xFLAG tag at the C-terminal end. Color keys are the same as in Fig 1A. (B) Relative body sizes of worms at the same developmental stage WT (WT set to 1.0). ***P < 0.001; ND: no difference (ANOVA followed by Tukey HSD). WT: N = 54. tm7125: N = 51. jj441: N = 51. jj411: N = 47. jj412: N = 41. (C) Table showing the penetrance of the Susm phenotype of smoc-1(TY) and smoc-1(EC) as compared to the smoc-1(0) worms. a The lack of M-derived CCs phenotype is not fully penetrant in sma-9(cc604) mutants. b Data from DeGroot and colleagues [12]. Statistical analysis was conducted by comparing double mutant lines with the sma-9(cc604) single mutants. ***P < 0.001; ND: no difference (unpaired two-tailed Student’s t test). Original data sets are in S1 Data. CC, coelomocyte; EC, extracellular calcium-binding; SMOC, secreted modular calcium-binding protein; TY, thyroglobulin type-1; WT, wild type. https://doi.org/10.1371/journal.pbio.3002272.g004
	Fig 5. SMOC-1, but not LON-2, binds to DBL-1 when expressed in S2 cells. (A) Diagrams of LON-2 and DBL-1 expression constructs used in the Drosophila S2 cell expression system. (B) Results of co-IP experiments testing the interaction between LON-2::Myc and V5::DBL-1 prodomain::FLAG::DBL-1 mature domain. IP with anti-Myc beads, anti-V5 beads or anti-FLAG beads and IB with anti-Myc, anti-V5, or anti-FLAG antibodies, as indicated. Experiments were independently repeated in triplicate, with representative results shown in this figure, and < points to faint bands that likely represent glycosylated LON-2. (C) Diagrams of SMOC-1 and DBL-1 expression constructs used in the Drosophila S2 cell expression system. (D) Results of co-IP experiments testing the interaction between HA::DBL-1 prodomain::FLAG::DBL-1 mature domain and different versions of SMOC-1::V5*. IP with anti-V5 beads or anti-FLAG beads and IB with anti-V5 or anti-FLAG antibodies, as indicated. The source of DBL-1 in these experiments was cell media, which does not contain full-length DBL-1, but only HA-tagged prodomain and FLAG-tagged mature domain. Experiments were independently repeated in triplicate, with representative results shown in this figure. Original images of western blots can be found in S1 Raw Images. co-IP, coimmunoprecipitation; EC, extracellular calcium-binding; IB, immunoblot; IP, immunoprecipitation; SMOC, secreted modular calcium-binding protein; TY, thyroglobulin type-1. https://doi.org/10.1371/journal.pbio.3002272.g005
	Fig 6. Structural modeling of interactions between SMOC-1 and LON-2, and between SMOC-1 and DBL-1. (A) Predicted structure of a complex formed between LON-2 and SMOC-1. The EC domain of SMOC-1 is predicted to interact with LON-2. (B) Predicted structure of a complex formed between SMOC-1 and a homodimer of the DBL-1 mature domain. Both the EC and TY domains of SMOC-1 are predicted to interact with DBL-1. (C) Multiple sequence alignment of the TY domains of SMOC-1 homologs using Clustal Omega (CLUSTAL O(1.2.4)). Red * marks the residues at the interface between SMOC-1 and DBL-1, as identified via ColabFold. Green colored boxes indicate residues (Y72, Y90, Y95, W97) mutated to generate the SMOC-1(M3) mutation. (D) Multiple sequence alignment of the EC domains of SMOC-1 homologs using Clustal Omega (CLUSTAL O(1.2.4)). Red * marks the residues at the interface between SMOC-1 and DBL-1, and blue * marks the residues at the interface between SMOC-1 and LON-2, as identified via ColabFold. In both C and D, dark shaded residues are identical, while light shaded residues are conserved, among all or most of the homologs. Blue colored boxes indicate residues (S152, S156, M160) mutated to generate the SMOC-1(M1) mutation, while red boxes indicate residues (F253, L257) mutated to generate the SMOC-1(M2) mutation. EC, extracellular calcium-binding; SMOC, secreted modular calcium-binding protein; TY, thyroglobulin type-1. https://doi.org/10.1371/journal.pbio.3002272.g006
	Fig 7. Structural modeling of interactions between SMOC and BMP homologs from both vertebrate and invertebrate species. (A) Diagrams of SMOC proteins from C. elegans, H. sapiens, X. laevis, and D. melanogaster, showing the unique arrangement of the TY and EC domains in each SMOC protein. (B) Predicted structures of complexes formed between homologs of CeSMOC-1 and mature DBL-1 from C. elegans, H. sapiens, X. laevis, and D. melanogaster. Predictions are similar between HsSMOC1 and HsSMOC2, but only HsSMOC1 is shown here. Predictions are also similar between BMP4 and BMP2 for H. sapiens and X. laevis SMOCs, but only BMP2 is shown here. Note that each of the BMP ligands is predicted to make a similar interaction with a TY domain of its corresponding SMOC-1 homolog. The interaction with the C-terminus of the EC domain appears to be somewhat less conserved, as it is present in X. laevis and D. melanogaster predictions, but not in the H. sapiens predictions. However, H. sapiens SMOC1 appears to replace the EC domain interaction with a portion of the SMOC1 polypeptide located in between the 2 TY domains. This additional interaction involving the linker in between TY domains is also found in the prediction of the X. laevis complex. The SMOC-1 homologs from H. sapiens, X. laevis, and D. melanogaster each contain 2 TY domains, and in each prediction both domains make a similar contact with each of the 2 BMP molecules in the BMP dimer. BMP, bone morphogenetic protein; EC, extracellular calcium-binding; FS, follistatin-like; SMOC, secreted modular calcium-binding protein; TY, thyroglobulin type-1. https://doi.org/10.1371/journal.pbio.3002272.g007
	Fig 8. Co-IP results testing the model for tripartite complex formation. (A) Predicted structure of a complex formed between LON-2, SMOC-1, and a homodimer of the DBL-1 mature domain. The membrane-anchoring region of LON-2 lies at the bottom of the panel. (B) The same structure prediction as in A, but shown from the “top.” (C) Diagrams of LON-2, SMOC-1, and DBL-1 expression constructs used in the Drosophila S2 cell expression system. (D) Results of co-IP experiments testing the interaction between LON-2::Myc and HA::DBL-1 prodomain::FLAG::DBL-1 mature domain in the presence or absence of SMOC-1::V5. IP with anti-FLAG beads, or anti-Myc beads, and IB with anti-Myc, anti-V5 or anti-FLAG antibodies, as indicated. Note that immunoprecipitation of FLAG::DBL-1mature domain with anti-FLAG beads can pull down LON-2::Myc only in the presence of SMOC-1::V5. No FLAG::DBL-1mature protein was detected when IP was performed using anti-Myc antibodies, very likely due to the low amount of FLAG::DBL-1mature protein in the co-IP experiments, as FLAG::DBL-1mature protein was not detectable in the Input lanes where approximately 1% of materials used for the co-IP experiments were loaded. Experiments were independently repeated in triplicate, with representative results shown in this figure. Original images of western blots can be found in S1 Raw Images. co-IP, coimmunoprecipitation; EC, extracellular calcium-binding; IB, immunoblot; IP, immunoprecipitation; SMOC, secreted modular calcium-binding protein; TY, thyroglobulin type-1. https://doi.org/10.1371/journal.pbio.3002272.g008
	Fig 9. The in vitro and in vivo consequences of mutations in SMOC-1 that affect either LON-2 binding or DBL-1 binding. (A) Diagrams of LON-2, DBL-1, WT, and mutant SMOC-1 expression constructs used in the Drosophila S2 cell expression system. (B) Results of co-IP experiments testing the interaction between LON-2::Myc and V5-tagged WT and mutant SMOC-1 proteins. IP with anti-V5 beads and IB with anti-Myc or anti-V5 antibodies, as indicated. Experiments were independently repeated in triplicate, with representative results shown in this figure. (C) Results of co-IP experiments testing the interaction between HA::DBL-1 prodomain::FLAG::DBL-1 mature domain and V5-tagged WT and mutant SMOC-1 proteins. IP with anti-V5 beads or anti-FLAG beads and IB with anti-V5 or anti-FLAG antibodies, as indicated. The source of DBL-1 in these experiments was cell media, which does not contain full-length DBL-1, but only HA-tagged prodomain and FLAG-tagged mature domain. Experiments were independently repeated in triplicate, with representative results shown in this figure. (D) DIC images of worms endogenously expressing SMOC-1(WT) [smoc-1(jj276)], SMOC-1(M1) [smoc-1(jj499 jj276)], or SMOC-1(M1+M2) [smoc-1(jj499 jj511 jj276)], showing the long body size of SMOC-1(M1) worms, as compared to SMOC-1(WT) and SMOC-1(M1+M2) worms. Scale bar represents 50 μm. (E, F) Relative body sizes of various strains at the same developmental stage (WT set to 1.0). Groups marked with distinct symbols are significantly different from each other (P < 0.001, in all cases when there is a significant difference), while groups with the same symbol are not. The following are exceptions: the P-value between jj499 jj510 and jj276 is 0.003, while the P-value between jj499 jj510 and jj499 jj511 is 0.63. Tested using an ANOVA with a Tukey HSD. WT: N = 22. tm7125: N = 33. jj276: N = 37. jj276/+ heterozygotes: N = 29. jj499: N = 37. jj500: N = 32. jj499/+ heterozygotes: N = 19. lon-2(e678): N = 30. jj499 jj510: N = 32. jj499 jj511: N = 27. Original data sets are in S1 Data. Original images of western blots can be found in S1 Raw Images. co-IP, coimmunoprecipitation; EC, extracellular calcium-binding; IB, immunoblot; IP, immunoprecipitation; SMOC, secreted modular calcium-binding protein; WT, wild type. https://doi.org/10.1371/journal.pbio.3002272.g009
	Fig 10. The in vitro and in vivo consequences of mutations in LON-2 that affect SMOC-1 binding. (A) Diagrams of SMOC-1, WT, and mutant LON-2 expression constructs used in the Drosophila S2 cell expression system. (B) Results of co-IP experiments testing the interaction between SMOC-1::V5 and Myc tagged WT and mutant LON-2 proteins. IP with anti-V5 beads or anti-Myc beads and IB with anti-V5 or anti-Myc antibodies, as indicated. Experiments were independently repeated in triplicate, with representative results shown in this figure. (C) DIC images of WT, lon-2(jj678) null, and lon-2(jj507) worms, showing their body sizes. Scale bar represents 50 μm. (D) Relative body sizes of worms at the same developmental stage (WT set to 1.0). ***P < 0.001; ND: no difference (ANOVA followed by Tukey HSD). WT: N = 21. e678: N = 31. jj507: N = 26. jj508: N = 27. Original data sets are in S1 Data. Original images of western blots can be found in S1 Raw Images. co-IP, coimmunoprecipitation; EC, extracellular calcium-binding; IB, immunoblot; IP, immunoprecipitation; SMOC, secreted modular calcium-binding protein; TY, thyroglobulin type-1; WT, wild type. https://doi.org/10.1371/journal.pbio.3002272.g010
	Fig 11. Overexpression of SMOC-1 and DBL-1 has an additive effect on body size. (A) DIC images of worms of various genotypes, including lon-2(0) null, smoc-1(OE), dbl-1(OE), and smoc-1(OE); dbl-1(OE) worms. Scale bar represents 50 μm. (B) Relative body sizes of various strains at the same developmental stage (WT set to 1.0). lon-2(e678) is a null allele of lon-2. jjIs5799 is an integrated multicopy array line that overexpresses SMOC-1::2xFLAG. jjIs6448 is an integrated multicopy array line that overexpresses DBL-1. For each of the genotypes except for WT, e678 and jjIs5799, 2 independent isolates of the same genotype were measured, and data were combined for statistical analysis. Groups marked with distinct symbols are significantly different from each other (P < 0.001, in all cases when there is a significant difference), while groups with the same symbol are not. The following are exceptions: the P-value between jjIs6448 and jjIs6448; e678 is 0.55, while the P-value between jjIs5799; e678 and jjIs6448; e678 is 0.007. Tested using an ANOVA with a Tukey HSD. WT: N = 28. e678: N = 37. jjIs5799: N = 39. jjIs5799; e678: N = 34. jjIs6448: N = 29. jjIs5799; jjIs6448: N = 45. Original data sets are in S1 Data. SMOC, secreted modular calcium-binding protein; WT, wild type. https://doi.org/10.1371/journal.pbio.3002272.g011
	Fig 12. A model for how SMOC-1 functions to regulate BMP signaling. (A) In WT animals, SMOC-1 is proposed to both negatively and positively regulate BMP signaling. For its negative role, SMOC-1 binds to LON-2/glypican and DBL-1/BMP to sequester DBL-1/BMP. In the meantime, SMOC-1 can also bind to DBL-1/BMP to promote BMP signaling. The positive and negative roles of SMOC-1 in WT animals balance each other out, leading to a WT body size. (B) In smoc-1(0) animals, both the positive and negative roles of SMOC-1 are gone, leading to a slightly small body size. (C–E) Removing LON-2 completely [as in lon-2(0)] or disrupting SMOC-1-LON-2 interaction [as in smoc-1(M1) or lon-2(mut)] eliminates the negative role of SMOC-1, leading to a long body size. (F) Weakening SMOC-1-DBL-1 interaction in the SMOC-1(M1) background [as in smoc-1(M1+M2)] significantly attenuates the positive role of SMOC-1, leading to a non-long, WT-like body size. BMP, bone morphogenetic protein; SMOC, secreted modular calcium-binding protein; WT, wild type. https://doi.org/10.1371/journal.pbio.3002272.g012

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