CHAPTER 1 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY

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1 CHAPTER 1 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY Andrew Beenken and Moosa Mohammadi* Department of Pharmacology, New York University School of Medicine, New York, New York, USA. *Corresponding Author: Moosa Mohammadi Moosa.Mohammadi@nyumc.org Abstract: klotho coreceptor proteins in order klotho ectodomain klotho complex and alleviate hypophosphatemia in renal Endocrine FGFs and Klothos, 2012 Landes Bioscience and Springer Science+Business Media. 1

2 2 ENDOCRINE FGFs AND KLOTHOS INTRODUCTION: AN OVERVIEW OF FGF-FGFR SIGNALING 1-3 Based on sequence homology and phylogeny, the eighteen mammalian FGFs are grouped 4-6 include the FGF1 FGF7 7, 10, 22; the FGF4 FGF8 FGF8, 17, 18; and the FGF9 FGF mesoderm induction, 10,11 somitogenesis, organogenesis, whereas including glucose, and serum phosphate/ vitamin D homeostasis antiparallel This 3 N-terminal region domain ,37,38 39,40 41,42 This D3 alternative splicing event mesenchymal tissues respectively. 41,43 Importantly, the D3 alternative splicing event 35

3 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 3 HS MODULATES FGF SIGNALING THROUGH MULTIPLE MECHANISMS N 49 HS impinges on FGF signaling through and 52, loop and the segment spanning the 10 to 12 strand. FGFRs also interact with HS via A loop, the A - B loop, and the B strand. and the two receptors additionally make contact with one another. 50,55 extracellular matrix, other on the A-loop tyrosines. A-loop tyrosine phosphorylation increases the intrinsic The phosphorylated tyrosines in 61,62 and CRKL, 63, this to increase its stimulate Ca Lastly, activated FGFR phosphorylates FRS2, 67 another adaptor protein that, unlike PLC and the phosphatase Shp2, 71 72

4 4 ENDOCRINE FGFs AND KLOTHOS Figure 1

5 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 5 Figure 1.. -sheets that compose the FRS2, and CRKL. PARACRINE FGFs MEDIATE A MESENCHYMAL-EPITHELIAL SIGNALING LOOP WITHIN TISSUES

6 6 ENDOCRINE FGFs AND KLOTHOS Figure FGF2 is in dark grey, the D2 and D3 domains atoms are shown. 1 2 loop and the segment spanning 10 to 32-35,37, segment spanning 10 to segment.

7 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 7 77 plays a key role in imparting the 10 and 12 strands in paracrine FGFs glycine in strand. Lastly, the side 55,78-80 and are expressed in either epithelial or mesenchymal compartments within organs. The It is well documented that FGF7 and FGF10, which are glands including lung, thyroid, pituitary, lacrimal and salivary glands. 84,86-90 In contrast, the 7,20,91,92 ENDOCRINE FGFs REGULATE KEY METABOLIC PROCESSES IN A KLOTHO-DEPENDENT FASHION 93 Later studies in turn induces phosphate wasting. 56,94,95 Shimada and colleagues showed that FGF23 96 through experiments on FGF21 22 and FGF19 25 The endocrine FGFs require klotho proteins as coreceptors in order to exert

8 8 ENDOCRINE FGFs AND KLOTHOS Figure 3.

9 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 9 Figure 3. -sheets are highlighted with grey in the alignment and the helical secondary structures in FGF19 and FGF23 are highlighted with dark grey. Numerous important support FGF19 s unusual 10 and the 10

10 10 ENDOCRINE FGFs AND KLOTHOS Figure 4. Paracrine FGFs mediate an epithelial-mesenchymal signaling loop. Ligands expressed in the epithelium signal through receptors expressed in the mesenchyme and vice versa. KL1 and KL2. 97 FGF19 and FGF21 require klotho, and FGF23 requires klotho 104,105 Klotho-dependency restricts expressed. klotho was originally discovered as an aging suppressor gene in mice klotho knockout mice. 106,107 Klotho-knockout mice, and FGFR4 knockout and klotho plays a vital role in serum phosphate activates FGFR1c in the kidney in an 104,105,111 thus promoting ,119 FGF19 reaches the liver via the hepatic portal vein where it activates hepatic FGFR4 in a klotho-dependent 99,100,103

11 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY Additionally, FGF19 acts to promote and it activates FGFR1c in adipocytes in a 98,99,101,102 to stimulate gluconeogenesis, ketogenesis and 22, TIO, 130, ,131 a disorder involving increased FGF inherited and tumor-induced phosphate wasting disorders as well as hypophosphatemia associated with other conditions such as organ transplantation and parenteral iron FTC patients. wasting disorders. Structure-Function Relationships of Endocrine FGFs HBS regions, namely the 1-10 and 12 strands 10 and

12 12 ENDOCRINE FGFs AND KLOTHOS FGFs. Moreover, the 1 56 FGF19 Structural Findings 137 In 10 and 12 strands is disordered, 137 In the second FGF19 crystal structure crystal displayed a well ordered region FGF19 structure to C the 10 -helix ( 10 the conserved in the 10 The 1 11 helix. In contrast to paracrine ligands where the 1 2 loop and 10 FGF23 Structural Findings

THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 13 Figure 5. 56 a cartoon. The sheets and the FGF19 C 1 2 loop and 10 1 2 10 1 2 10 12 region.

13 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 13 Figure a cartoon. The sheets and the FGF19 C 1 2 loop and region. sequence divergence at the 10 C in their 10 paracrine FGFs and instead PROCHECK assigns a g-helix to the C-terminal region Compared to paracrine FGFs, FGF23 has a very short 9 10 loop which is needed

14 ENDOCRINE FGFs AND KLOTHOS Figure 6. 56 as a cartoon. The sheets and shown in light grey and FGF23 in dark grey.

14 14 ENDOCRINE FGFs AND KLOTHOS Figure as a cartoon. The sheets and shown in light grey and FGF23 in dark grey. even a one residue insertion in the loop and and Arg-48 and Asn-49 in 1 THE MOLECULAR BASIS FOR THE FGF19 SUBFAMILY S KLOTHO CORECEPTOR REQUIREMENT 55 illuminates the impact

THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 15 10 80 55,78,79 This 56 56 56 It

15 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY ,78,79 This It remains in their signaling. 10 and 12 in FGF19 and FGF23 displays two 10 the 10 Figure 7. 55

16 16 ENDOCRINE FGFs AND KLOTHOS region is identity in the 10 STRUCTURAL BASIS FOR THE SPECIFICITY AND AFFINITY OF ENDOCRINE FGFs BINDING TO FGFR did not induce hypophosphatemia. 111 knockout mice, , ,37-39 have shown that the extent to which 1 strand pairs with 4 plays a decisive role in the 1 strands pairing with C - E 1 strand C - 1 3,98-101,

17 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY CHARACTERIZATION OF THE BINDING OF FGF23 TO KLOTHO 94 poorly to klotho complex a de novo klotho in the klotho. klotho phosphorylation

18 18 ENDOCRINE FGFs AND KLOTHOS PHARMACOLOGICAL IMPACT OF STRUCTURAL INSIGHTS INTO FGF19 SUBFAMILY phosphate therapy along with 1,25-dihydroxyvitamin D 3 phosphate wasting such as occur in XLH. with FGFR1c- klotho dependent and klotho independent CONCLUSION klotho, FGF21-FGFR1c- klotho, and FGF23-FGFR1c- klotho when and FGF21 through their respective cognate receptors, FGFR4 and FGFR1c. The structures klotho proteins with FGFR and endocrine FGFs. 51

THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 19 Figure 8. 55 and is depicted in dark grey. 140 klotho and is depicted in light grey.

19 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 19 Figure and is depicted in dark grey. 140 klotho and is depicted in light grey. through a single Arg Val mutation in the FGF10 HBS. This mutation reduced FGF10 s REFERENCES Cancer Res 1993; 60: Goriely A, Hansen RM, Taylor IB et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic

20 20 ENDOCRINE FGFs AND KLOTHOS 11. Niswander L, Tickle C, Vogel A et al. FGF-4 replaces the apical ectodermal ridge and directs outgrowth

21 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY Mohammadi M, Dionne CA, Li W et al. Point mutation in FGF receptor eliminates phosphatidylinositol turnover and Ca2

22 22 ENDOCRINE FGFs AND KLOTHOS 2001; 24: Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet 2000; rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 2002;

23 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY 23 induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; -dependent phosphate cotransport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem 2003;

24 24 ENDOCRINE FGFs AND KLOTHOS activation. J Biol Chem 2009.

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