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Alisha Parveen et al, 2019;2(1):03–17.

Collagen-specific chaperone, heat shock protein 47 kDa (HSP47)–pathway and expression patterns in cancer

Alisha Parveen1, Rajesh Kumar2, Sukant Khurana3, Abhishek Kumar4*

Correspondence to: Abhishek Kumar

*Department of Genetics and Molecular Biology in Botany, Institute of Botany, Christian-Albrechts-University at Kiel, Germany.

Email: abhishek.abhishekkumar [at]

Full list of author information is available at the end of the article.

Received: 03 November 2018 | Accepted: 01 December 2018



Human serpin gene SERPINH1 encodes for a non-inhibitory serpin shock protein 47 kDa (HSP47) a client-specific chaperone, which is a hallmark in the collagen biosynthesis. Till today, there is no comprehensive study on the protein network for human HSP47. Thus, the current study aimed at studying the pathway and expression patterns observed in collagen-specific chaperone, HSP47 in relation to cancer.


The study used STRING 10 ( in finding putative protein interaction partners of human HSP47. Also, database HMMER3 ( with Pfam 32.0 (September 2018) dataset was used in identifying Pfam protein domains from proteins interacting with HSP47. The dbDEPC3.0 was used for the evaluation of expression patterns of HSP47 in different cancer. Further three online resources, namely, human protein atlas (, genotype-tissue expression (, and FANTOM5 project ( was used to examine HSP47 expression in normal human tissues.


Upon constructing protein interactive map of human HSP47, the study found that a set of molecular chaperones as interaction partners of HSP47, which included two copies each of cAMP response element binding proteins, HSP27, HSP40, HSP70, HSP90, ubiquitin proteins and one copy each of cartilage associated protein, HSPH1, HSBP1, FK506-binding protein 4, kruppel-like factor, peptidyl-prolyl isomerase, and Prolyl 4-hydroxylase beta subunit.


The study found a cocktail of different chaperones interacting with HSP47, originated at different time points from prokaryotes to eukaryotes. Overall, the study was successful in finding HSP47 expression patterns among several normal tissues using three different publicly available datasets. It also assessed the expression pattern of HSP47 in human cancer types. These findings will encourage further studies focusing on the role of HSP47 in human diseases.


HSP47, SERPINH1, protein-protein interaction, cancer, expression patterns.


Heat shock protein 47 kDa (HSP47) serves as an endoplasmic reticulum (ER)-residing collagen-specific chaperone and has the cavalier role in collagen biosynthesis and its structural assembly process (1,2). HSP47 protein is the product of the human SERPINH1 gene, which belongs to the group V6 in the indel-based group-wise classification of vertebrate serpins (3). Structurally, HSP47 is a typical serpin domain (Pfam ID—PF00079), composed of three β-sheets (s) and nine α-helices (h) as sA-sC and hA-hI, respectively (4). HSP47 has a non-inhibitory reactive center loop (1). Previous reports have mainly focused on the role of HSP47 in the collagen biosynthesis and in exploring its evolutionary history (1). Human HSP47 has been reported to be associated with several human diseases, including familial connective tissue disorder Osteogenesis imperfecta (OI) (5) and various types of cancer (6). Till today, there has been no study conducted exclusively in studying the protein interactome of HSP47. To resolve this issue, the current study team has constructed interaction maps of HSP47 to identify the top 20 interactions partners, most of which include heat shock proteins. The study team also examined the expression pattern of HPS47 in the different types of cancer and normal tissues.

Materials and Methods

The putative protein interaction partners of human HSP47 was detected using online database STRING 10 (website: (7)) with confidence score higher than 0.9 with searching options of top 20 interaction partners. The study identified Pfam protein domains from proteins interacting with HSP47 using HMMER3 with Pfam 32.0 (September 2018) dataset. Evaluation of HSP47 expression in different cancers tissues and normal tissues was performed using dbDEPC 3.0, the database of differential expression of the protein in cancer (8). The current study also examined HSP47 expression in normal human tissues using three online resources, namely, human protein atlas (HPA,, genotype-tissue expression (GTEx,, and FANTOM5 project (

Results and Discussion

A cocktail of different chaperones interacts with HSP47

To evaluate the protein interaction partners of HSP47, the study team constructed the interactome map of human HSP47 protein. Remarkably top 20 protein–protein interaction partners (confidence score ≥ 0.9) were found to be different types of molecular chaperones (Figure 1; Table 1). This suggested that a cocktail of different molecular chaperones is essential for maintaining proper physiology of HSP47 in the ER. On plotting these proteins on the evolutionary scale, it was evident that these partners are originated at different time points (Figure 2). Furthermore, three of these proteins were found to be highly conserved across different evolutionary lineages (marked by the green box in Figure 2).

HSP47 interaction partners have protein domain level similarities

These HSP47 interaction partners include two paralogs involved in histone acetylating process: cAMP response element binding (CREB) binding protein (CREBBP) and E1A binding protein p300 (EP300) (9). These two proteins were closely related in size where CREBBP and EP300 were 2,442 and 2,414 residues long, respectively. These two proteins were also found to possess multiple Pfam domains, such as Zf-TAZ (Pfam ID—PF02135.15), KIX (PF02172.15), Bromo (PF00439.24), unknown domain (PF06001.12), HAT_KAT11 (PF08214.10), ZZ (PF00569.16), and other unknown domain (PF09030.9), respectively (Figure 3A–B). Both CREBBP and EP300 proteins work as histone acetyltransferases and are involved in transcription regulation and/or cell cycle progression by modulating the chromatin structure (9). Furthermore, they also act as prominent chromatin remodelers operating as scaffolds, which stabilize other protein–protein partners with the formation of transcription complexes. Both of them are also involved in crucial physiological roles, including development, growth, and homeostasis (9). CREBBP and EP300 genes are localized in the human genome (Table 1) on the chromosomes 16 (cytoplasmic band 16p13.3) and 22 (22q13.2), respectively. Mutations in these genes cause a rare neurodevelopmental syndrome known as the Rubinstein–Taybi syndrome (RSTS, OMIM #180849, #613684), which is characterized by deformity in facial appearance, skeletal and dysmorphic abnormalities, microcephaly, enlargement of thumbs and first toes, and impaired intellectual and postnatal growth (10). Cartilage associated protein (CRTAP) reported was 401 amino acids long without any known protein domain (Figure 3C). It is encoded by the CRTAP gene localized on the human chromosome 3 (cytoplasmic band 3p22.3, Table 1). CRTAP forms the collagen prolyl 3-hydroxylation complex with P3H1 and cyclophilin B (CyPB) in the ER, which 3-hydroxylates the pro986 residue of α1(I) and α1(II) collagen chains (11). CRTAP is also associated with a small percentage (5%–7%) of patients with severe to lethal OI types VII (OMIM #610682). Five known mutations are reported in the CRTAP gene, leading into either prevention of the production of any cartilage associated proteins, or reduction in the production of cartilage associated proteins. Irregularities in the production of cartilage associated proteins cause problems information of collagen, which ultimately results in the severe form of OI (11).There have been two HSP40 proteins found to be involved in HSP47 interaction, including DnaJ (Hsp40) homolog subfamily B member 1 (DNAJB1) and member 6 (DNAJB6) of residue size of 326 and 340. DNAJB1 possesses two protein domains as DnaJ (PF00226. 31) in the N-terminal end (4–65 residues) and DnaJ_C (PF01556.18) in the C-terminal end (164–323 residues), while DNAJB6 only harbors DnaJ (PF00226.31) in the N-terminal end (3–66) (Figure 3D and E). These two proteins are encoded by genes DNAJB1 and DNAJB6, respectively, and these genes are localized on human chromosomes 19 (19p13.12) and 7 (7q36.3) (Table 1). J-domain is highly conserved domains amongst hsp40 proteins, which is associated with protein folding and protein disaggregation along with HSP70 (12,13). These two proteins are associated with human diseases resulted due to impaired protein folding (14,15). FK506-binding protein 4 (FKBP4) is 59 kDa immunophilin protein. FKBP4 protein is 459 amino acids long composed of two FKBP_C (PF00254.28) domains in the regions of 44–134 and 162–249 residues and two tetratricopeptide repeat domains [tetratricopeptide repeat (TPR)_1, PF00515.28, and TPR_2, PF07719.17] in the regions of 321–352 and 354–386 (Figure 3F). These TPRs are required for interactions with HSP70 and HSP90 as co-chaperones (16). FKBP4 is majorly involved in protein folding and cellular trafficking (16). This protein is encoded by FKBP4 gene mapped in the region of 12p13.33 on human chromosome 12 (Table 1). There are two HSP70 homologs as interaction partners of HSP47 as heat shock 70kDa protein 6 (HSPA6) and HSPA8 (also known as heat shock cognate 71 kDa protein, Hsc70), both of these proteins harbor HSP70 (PF00012.19) protein domain (Figure 3G and H). These two proteins are encoded by the genes- HSPA6 and HSPA8, which are mapped to chromosomal regions 1q23.3 and 11q24.1 in the human genome, respectively (Table 1). These two ubiquitous molecular chaperones (HSPA6 and HSPA8) are members of core Hsp70 machinery and these proteins have critical roles in proper protein folding, protein degradation, protein translocation across membranes, and protein–protein interactions (17). Another interaction partner of HSP47 network is heat shock 105 kDa/110 kDa protein 1 (HSPH1), which also contains HSP70 (PF00012.20) in the region of 3–704 with total protein length 858 (Figure 3I). Gene HSPH1 mapped on13q12.3 genomic fragment (Table 1), which encodes for HSPH1 protein. The other two very important heat-shock protein 27 (HSP27) homologs include heat shock factor binding protein 1 (HSPB1) and 2 (HSPB2) with size 205 and 182 amino acids with a protein domain HSP20 (PF00011.20) in the region of 88–183 and 70–162, respectively (Figure 3J and K). HSPB1 gene is localized on human chromosome 7 (7q11.23), while HSPB2 is mapped to 11q23.1 region in chromosome 11 (Table 1). It encodes for an enzyme, which is a member of a heat shock protein family. Under environmental stress, HSPB1 translocates from the cytoplasm to nucleus and helps other protein in error-free folding. HSPB1 gene is majorly involved in the differentiation of a wide range of cell type. Mutation in this gene leads to Charcot–Marie–Tooth Disease, Axonal, Type 2F, and distal hereditary motor neuropathy, Type IIb diseases. HSPB1 is also involved in major cellular processes, including apoptosis, thermotolerance, protein disaggregation, and cell differentiation and development. HSPB2 has a crucial role in binding and activating myotonic dystrophy protein kinase; hence, it is also called as myotonic dystrophy kinase binding protein (MKBP). This protein HSPB1/MKBP is a major player in maintenances of muscle structure and function (18). HSP27 has a highly conserved α-crystallin domain that is enriched with β-sheet structures. Small heat shock proteins (sHSPs) bind to aggregated proteins in ATP-independent manner and which are subsequently tackled by either by HSP70 system (Hsp70 plus Hsp40 system) or Hsp70/104 bichaperone (19) system for protein disaggregation. Disaggregated proteins either get refolded back into native proteins or degraded by autophagy and/or proteasomal system. In addition, HSP27 recently was reported to be involved in cancer-related retinopathy, suggesting its role in developing cancer therapeutics (20). HSBP1 gene is localized in the genomic fragment of 16q23.3 on the chromosome 16 (Table 1), encodes for HSBP1 protein, which is 76 amino acids long with HSBP1 (PF06825.12) domain in the region of 10–60 (Figure 3L). HSBP1 is a member of the sHSPs family and this protein prevents the aggregation of denatured and stress-induced misfolded proteins (21). There are two HSP90 homologs acting as protein–protein interaction partners: HSP90AA1 (or Hsp90α) and HSP90AB1 (Hsp90β), belong to HSP90 family, which is a well-characterized, well-documented conserved and critical eukaryotic chaperone family (22). These homologs HSP90AA1 and HSP90AB1 are mapped into the human chromosomes 14 (14q32.31) and 6 (6p21.1), respectively (Table 1). These two proteins have two types of protein domains, such as HATPase_C (PF02518.25) and HSP90 (PF00183.17) in the N-terminal and the C-terminal end (Figure 3M and N). HSP90 proteins are required for the proper function of other chaperones. These HSP90 proteins are essential for the maturation, structural maintenance and protein folding, intracellular trafficking, and other signal transduction events (22,23). HSP90AB1 was shown to be overexpressed during cancer, which prevents misfolding, and degradation of both mutated (for example Ras and p53) and over-expressed oncoproteins (for example p53 and Her2) (24). Leucine proline-enriched proteoglycan 1 (LEPRE1, leprecan) gene is located on the human chromosome1 (cytoplasmic location 1p34.2) (Table 1). LEPRE1 encodes prolyl 3-hydroxylase 1 (P3H1), which is a member of collagen prolyl hydroxylase family with 736 amino acid long and it possesses a single domain of 96 residues long as OG-Fe(II) oxygenase superfamily (2OG-FeII_Oxy_3, PF13640.5) in the region of 584–661 (Figure 3O). Peptidyl-prolyl isomerase B (PPIB)/CyPB plays an instrumental role in the formation of the collagen prolyl 3-hydroxylation complex with P3H1 and CRTAP in the ER (11).The activity required for proper collagen synthesis and assembly (11). Mutation in this gene is associated with OI type VIII.

Figure 1. Protein interactome network of human HSP47 revealing several molecular chaperones as interaction partners for HSP47: This network is produced with the help of STRING 10 (7) with confidence score >0.9. (A) Interactome of collagen-specific chaperone and its assistance in collagen triplet formation. (B) Details of top HSP47-protein interaction partners with their confidence scores. Evidences are marked by a black dot.

Table 1. Top protein-protein interaction partners of HSP47.

Figure 2. Origin of protein interactome partners of collagen-chaperone: HSP47 depicts a mixture of interactions originated at different time frames, the couple together with ancient and recently originated proteins: Three proteins are highly conserved from archaea to human (marked in green boxes) and five are missing in fungi (yellow triangle).

Kruppel-like factor 13 (KLF13) protein is encoded by KLF13 gene is localized on human chromosome 15 (Table 1) and KLF13 protein is 288 amino acids long with three copies of Zf-C2H2 (PF00096.25) domain from mid to the C-terminal end (Figure 3P). It is a member of KLFs family of Cys2-His2 (C2H2) zinc-finger transcription factors and it has play function in a myriad of physiological roles during cell differentiation and development processes (25). P4HB gene is localized on human chromosome 17 (cytoplasmic ban 17q25.3), which encodes for prolyl 4-hydroxylase beta subunit (P4HB) protein of size 508 amino acids with three protein domains made of two thioredoxin (PF00085.19) in the N-terminal (25–131 residues) and the C-terminal ends (368–472 residues) and one thioredoxin_6 (PF13848.5) in the middle located in 161–345 residues (Figure 3Q). This protein is a member of the disulfide isomerase family and it is also called protein disulfide isomerase (PDI). P4HB/PDI is the ubiquitously expressed protein which helps in the correction of disulfide bridges in nascent polypeptide chains (26). Hence, P4HB/PDI plays an instrumental role in the protein folding and the cellular concentration of this protein is critical for protein aggregation/disaggregation (26). Mutations in this protein are involved in a new form of OI-like disorder, known as Cole-Carpenter syndrome (26). PPIB gene is located on human chromosome 15 (cytoplasmic band 15q22.31), which encodes for PPIB of size 216 residues with pro-isomerase (PF00160) domain in the region of 47–204 residues (Figure 3R) and it is also known as cyclophilin B (CyPB). PPIB/CyPB plays an instrumental role in the formation of the collagen prolyl 3-hydroxylation complex with P3H1 and CRTAP in the ER (11). Mutational variation in this gene leads to recessive forms of OI. The PPIases enzyme helps in the catalysis process of the cis-trans isomerization of proline imidic peptide bonds in proteins and it ultimately assists in protein folding and provides structural stability (11). PPIB is a member of peptidyl-prolyl cis-trans isomerase (PPIase) with a β-barrel structure like cyclophilin and is localized inside the ER lumen (27). Due to its localization to this specialized cellular compartment, it is involved in many biological processes, such as post-translational modification and proper folding of proteins, such as type I collagen (28).

Finally, there are two ubiquitin proteins, which exists as interaction partner of HSP47: ubiquitin B (UBB) and ubiquitin C. These proteins are variable in protein length with 229 and 685 amino acids and similarly these two possess three and nine ubiquitin domains (72 amino acids each; PF00240.22), respectively (Figure 3S and T). UBB and UBC are encoded by UBB and UBC genes mapped on chromosomes 17 (17p11.2) and 12 (12q24.31), respectively (Table 1). They are highly conserved eukaryotic proteins involved in protein ubiquitination, which is a multifaceted dynamic post-translational change occurring with help of the ubiquitin code present in the 72 amino acids of ubiquitin domain (29) with Pfam ID—PF00240.22. The protein ubiquitination results in clearance of aberrant proteins for their possible degradation by the proteasome and hence, this process is associated with various physiological cycles and in regulations of various signaling pathways (29). Mutations in these two ubiquitins are related to different human diseases, including Huntington’s disease, Alzheimer’s disease, and polyglutamine disease (30). The findings of the study are coinciding with other interactome analyses that chaperones interact with each other in the large interactome, also called as chaperome (31). Previously, it is known that and CRTAP HSP47, P3H1, and PPIB/CyPB plays an instrumental role in the formation of the collagen prolyl 3-hydroxylation complex in the ER (11). Several of HSP47 interaction partners also are markers of the panel of osteogenesis imperfecta (Version 1.12) under Rare Disease 100 K ( Taken together, the protein–protein network of HSP47 reported in the current study is a critical protein network in collagen-related disorders. Hence, remaining members of interactions partners must be taken into consideration for future evaluations. Expression of HSP47 in different cancers tissues and normal tissues

Figure 3. Overview of protein domain architecture of top 20 proteins interacting with HSP47: Pfam protein domains and corresponding Pfam IDs are listed in the box: (A) CREBBP—CREB binding protein; (B) EP300—E1A binding protein p300; (C) CRTAP—Cartilage associated protein; (D) DNAJB1—DnaJ (Hsp40) homolog subfamily B member 1; (E) DNAJB6—DnaJ (Hsp40) homolog subfamily B member 6; (F) FKBP—FK506-binding protein 4; (G) HSPA6—Heat shock 70 kDa protein 6; (H) HSPA8—Heat shock 70 kDa protein 8; (I) HSPH1—Heat shock 105 kDa/110 kDa protein 1; (J) HSPB1—heat shock protein beta-1; (K) HSPB2—heat shock protein beta-2; (L) HSBP1—heat shock factor binding protein 1; (M) HSP90AA1—heat shock protein Hsp 90-alph(cytosolic), class A member 1; (N) HSP90AB1—heat shock protein Hsp 90-alpha (cytosolic), class B member 1; (O) LEPRE1—Leucine proline-enriched proteoglycan (leprecan) 1; (P) KLF13—Kruppel-like factor 13; (Q) P4HB—Prolyl 4-hydroxylase beta subunit; (R) PIPB—Peptidyl-prolyl isomerase B; (S) UBB—Ubiquitin B; (T) UBC—Ubiquitin C.

It is also important to know, the expression pattern of HSP47 in different cancer types. To evaluate expression patterns of HSP47, the study team extracted data from the database of differential expression of the protein in cancer, dbDEPC 3.0 (8). In 11 types of cancer, HSP47 was found to be up-regulated among four cancers types based on the number of experiments. The cancer types included meningioma, colorectal cancer, hepatocellular carcinoma, and breast cancer (Figure 4; Table 2). HSP47 was found to be down-regulated in chordoma, lung adenocarcinoma, and urinary bladder neoplasms (Figure 4; Table 2). These inferences made us further investigate that how the expression patterns of HSP47 are in different normal human tissues. To evaluate expression pattern, the study group scanned three large resources of human gene expression datasets as HPA (, GTEx (, and FANTOM5 project ( Upon evaluating protein level expression of HPS47 using the HPA resource, it was found that human HSP47 protein is highly expressed in the normal tissues of lung, kidney, breast, endometrium, ovary, and placenta (Figure 4B), whereas expression of HPS47 was found as medium levels in tissues of tonsil, smooth muscle, oral mucosa, esophagus, testis, vagina, cervix (uterine), soft tissue, and skin (Figure 4B). Low level of expression of HSP47 was found in tissues of the adrenal gland, bronchus, cerebral cortex, and colon (Figure 4B). Furthermore, the current study also examined Ribonucleic acid sequence (RNA-Seq) data for HSP47 from the HPA resource. Placenta tissues had the highest expression of RNA seq levels with 329.1 transcripts per million (TPM), whereas other normal tissues with higher level of expression pattern (>100 TPM) included smooth muscle (270.5 TPM), cervix, (uterine, 179.6 TPM), endometrium (169.8 TPM), adipose tissue (145.4 TPM), appendix (135.9 TPM), and gallbladder (108.8 TPM). Fourteen tissues had medium levels of HSP47 expression (<100 and >35 TPM) with top two being urinary bladder (93 TPM) and ovary (80.6 TPM) and the last two being rectal (38 TPM) and colon tissues (35.4 TPM). Sixteen tissues had low levels of HSP47 expression (<35 TPM) with top two being epididymis (31.1 TPM) and parathyroid gland (29 TPM) and the last two being pancreas (four TPM) and bone tissues (2.2 TPM). Using FANFOM5 dataset, the study found that HSP47 to be highly expressed (>100 tags per millions) among normal tissues, including vagina, placenta, cervix (uterine), ovary, breast, thyroid gland, and urinary bladder (Figure 4E). The study also found medium (>100 tags per millions) and lower levels of HSP47 expression in 19 and 10 tissues types, respectively (Figure 4E).

Figure 4. Overview of different expression patterns of human HSP47 in cancer and different normal tissue types: (A) Summary of HSP47 expression pattern in different cancer types. This expression pattern was deduced from dbDEPC 3.0 (8). (B) Summary of human HSP47 protein expression patterns in different normal tissues derived from HPA ( (C) Overview of human HSP47 expression patterns using RNA-Seq data from HPA and expression values depicted as mean TPM, corresponding to mean values of the different individual samples from each tissue types. (D) Summary of RNA-seq based HSP47 expression patterns in different normal tissues and the values are shown as median reads per kilobase per million mapped reads (RPKM), derived from the GTEx ( datasets. (E) Overview of the expression pattern of HSP47 in normal human tissues reported as tags per million extracted through cap analysis of gene expression (CAGE) in the FANTOM5 project data ( Similar functional tissue groups are color coded with same colors in B–E.

Table 2. Overview of differential expression patterns of HSP47 in different cancer types.


Overall, the study was successful in finding HSP47 expression patterns among several normal tissues using three different publicly available datasets. It also assessed the expression pattern of HSP47 in human cancer types. These findings will encourage further studies focusing on the role of HSP47 in human diseases, along with our recent study of pathogenic mutational hotspot profilings of HSP47 (32).



Declaration of conflicting interests

The authors of this article have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

Ethical approval

Not applicable.

Consent for publication

This study does not involve patients and hence consent is not required.

Author details

Alisha Parveen1, Rajesh Kumar2, Sukant Khurana3, Abhishek Kumar4

  1. Medical Research Center, University of Heidelberg, Mannheim, Germany
  2. Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany
  3. Pharmacology Department, Central Drug Research Institute, Lucknow, Uttar Pradesh, India
  4. Department of Genetics and Molecular Biology in Botany, Institute of Botany, Christian-Albrechts-University at Kiel, Germany


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